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GSK-2816126

June 14, 2016 4:16 am / Leave a comment

GSK-2816126

N-[(1,2-Dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl]-3-methyl-1-[(1S)-1-methylpropyl]-6-[6-(1-piperazinyl)-3-pyridinyl]-1H-indole-4-carboxamide, GSK 126, GSK 2816126, GSK 2816126A

N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-((1S)-1-methylpropyl)-6-[6-(1-piperazinyl)-3-pyridinyl]-1H-indole-4-carboxamide

Formula	C₃₁H₃₈N₆O₂
Formula Wt.	526.67

An histone-lysine n-methyltransferase EZH2 inhibitor potentially for the treatment of B-cell lymphoma.

Research Code GSK-2816126; GSK-126; 2816126

CAS No. 1346574-57-9

Originator GlaxoSmithKline
Class Antineoplastics
Mechanism of Action EZH2 enzyme inhibitors; Histone modulators

Phase I Diffuse large B cell lymphoma; Follicular lymphoma
Preclinical Acute myeloid leukaemia

Most Recent Events

31 Mar 2014 Phase-I clinical trials in Follicular lymphoma (Second-line therapy or greater) in USA and United Kingdom (IV)
31 Mar 2014 Phase-I clinical trials in Diffuse large B cell lymphoma (Second-line therapy or greater) in USA and United Kingdom (IV)
16 Jan 2014 Preclinical trials in Diffuse large B cell lymphoma & Follicular lymphoma in United Kingdom (IV)

GSK-126 is an inhibitor of mutant EZH2, a histone methyltransferase (HMT) that exhibits point mutations at key residues Tyr641 and Ala677; this compound does not appreciably affect WT EZH2. EZH2 is responsible for modulating expression of a variety of genes. GSK-126 competes with cofactor S-adenylmethionine (SAM) for binding to EZH2. GSK-126 displays anticancer chemotherapeutic activity by inhibiting proliferation in in vitro and in vivo models of diffuse large B-cell lymphoma.

SYNTHESIS

PATENT

CN 105541801

https://www.google.com/patents/CN105541801A?cl=zh

Example 79: Add (S) in a three-necked flask 100 Qiu – bromo – Shu – (isobutyl) – N – ((4,6-dimethyl-2-oxo -l, 2- dihydropyridin-3-yl) methyl) -3-methyl-1 hydrogen – indole carboxamide (365mg, 0.82mmol), 2- (piperazin-1-yl) pyridine-5-boronic acid pinacol ester (309mg, 1.07mmol, 1 · 3eq), potassium phosphate (522mg, 2.46mmol, 3eq), water, and I, 4- diepoxy-hexadecane as the solvent. Then, under nitrogen was added [I, Γ- bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (53.9mg, 0.066mmo 1), and at 90 ° C reaction, to give the desired product after purification 400mg (92% yield). Goo NMR (500MHz, DMSO- (I6) JO.70-0 · 78 (ιή, 3H), 1.37-1.44 (m, 4H), 1.75-1.87 (m, 2H), 2.11 (s, 3H), 2.16 ( s, 3H), 2.22-2.27 (m, 3H), 2.77-2.85 (m, 4H), 3.41-3.49 (m, 4H), 4.35 (d, J = 5.31Hz, 2H), 4.56-4.68 (m, lH), 5.87 (s, 1H), 6.88 (d, J = 8.84Hz, 1H), 7.17 (d J = 1.52Hz, 1H), 7.26 (s, lH), 7.73 (d J = 1.26Hz, 1H) , 7.91 (dd, J = 8.84Hz, lH), 8.16 (t, J = 5.05Hz, lH), 8.50 (d, J = 2.53Hz, lH); 13C NMR (125MHz, DMSO- (I6) Sll .6 , 12.6,19.1, 19.9,21.7,30.4,35.9,46.3,46.9,52.4,107.6,108.2,108.5,110.6,116.9,122.6,123.8, 130.6,131.5,136.7,138.6,143.5,146.4,150.2,159.2,164.0 , 169.6.

PATENT

WO 2013067296

Examples 267 and 268

(S)-6-bromo-1 -(sec-butyl)-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-3- methyl-1 H-indole-4-carboxamide (Ex 267) and (R)-6-Bromo-1 -(sec-butyl)-N-((4,6- dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-3-methyl-1 H-indole-4-carboxamide (Ex 268)

6-Bromo-1-(sec-butyl)-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methy methyl-1 H-indole-4-carboxamide (racemic mixture, 1.9 g) was resolved by chiral HPLC (column : Chiralpak AD-H, 5 microns, 50 mm x 250 mm, UV detection :240 nM, flow rate: 100 mL/min, T = 20 deg C, eluent: 60:40:0.1 n-heptane:ethanol:isopropylamine

(isocratic)). For each run, 100 mg of the racemic compound was dissolved in 30 volumes (3.0 ml.) of warm ethanol with a few drops of isopropylamine added. A total of 19 runs were performed. Baseline resolution was observed for each run. The isomer that eluted at 8.3-10.1 min was collected (following concentration) as a white solid, which was dried at 50 °C (< 5 mm Hg) to afford 901 mg, and was determined to be the S isomer^* (Ex. 267; chiral HPLC: >99.5% ee (no R isomer detected). The isomer that eluted at 10.8-13.0 min was collected as a white solid, which was dried at 50 °C (< 5 mm Hg) to afford 865 mg, and was determined to be the R isomer^* (Ex. 268; chiral HPLC: 99.2% ee; 0.4% S isomer detected). ¹H NMR and LCMS were consistent with the parent racemate.

* The absolute configuration was determined by an independent synthesis of each enantiomer from the corresponding commercially available homochiral alcohols via Mitsunobu reaction. The sterochemical assignments were also consistent by vibrational circular dichroism (VCD) analysis.

Example 269

1-(sec-butyl)-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-3-methyl-6-(6- (piperazin-1 -yl)pyridin-3-yl)-1 -indole-4-carboxamide

Added sequentially to a reaction vial were 6-bromo-1 -(sec-butyl)-N-((4,6-dimethyl- 2-OXO-1 , 2-dihydropyridin-3-yl)methyl)-3-methyl-1 H-indole-4-carboxamide (0.15 g, 0.338 mmol), 1-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (0.127 g, 0.439 mmol), and potassium phosphate (tribasic) (0.287 g, 1.350 mmol), followed by 1 ,4- Dioxane (3 mL) and water (0.75 mL). The suspension was stirred under N₂ degassing for 10 min., and then added PdCI₂(dppf)-CH₂CI₂adduct (0.028 g, 0.034 mmol). The reaction vial was sealed, placed into a heat block at 95 °C, and stirred for 1.5 h. The contents were removed from heating and allowed to cool to room temperature. The aq layer was removed from bottom of the reaction vial via pipette. The reaction mixture was diluted into EtOAc (20 mL) followed by addition of 0.2 g each of Thiol-3 silicycle resin and silica gel. The volatiles were removed in vacuo and the residue dried on hi-vac for 1 h. The contents were purified by silica gel chromatography (dry loaded, eluent : A:

Dichloromethane, B: 10% (2M Ammonia in Methanol) in Chloroform, Gradient B: 8- 95%). The obtained solid was concentrated from TBME and dried in vacuum oven at 45 °C for 18 h. The product was collected as 129 mg (70%). ¹H NMR (400 MHz, DMSO-d6) δ ppm 0.73 (t, J=7.33 Hz, 3H), 1.40 (d, J=6.57 Hz, 3H), 1.80 (dq, J=10.07, 7.08 Hz, 2H), 2.1 1 (s, 3H), 2.14 – 2.19 (m, 3H), 2.24 (s, 3H), 2.76 – 2.85 (m, 4H), 3.41 – 3.49 (m, 4H), 4.35 (d, J=5.05 Hz, 2H), 4.54 – 4.67 (m, 1 H), 5.87 (s, 1 H), 6.88 (d, J=8.84 Hz, 1 H), 7.17 (d, J=1.26 Hz, 1 H), 7.26 (s, 1 H), 7.73 (d, J=1.26 Hz, 1 H), 7.91 (dd, J=8.84, 2.53 Hz, 1 H), 8.16 (t, J=5.05 Hz, 1 H), 8.50 (d, J=2.53 Hz, 1 H), 1 1.48 (br. s.,1 H) ; LCMS MH+ =527.3.

Example 270

A/-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-3-methyl-1 -[(1 S)-1 -methylpropyl]-6- [6-(1-piperazinyl)-3-pyridinyl]-1 H-indole-4-carboxamide

To a 30 mL microwave vial were added (S)-6-bromo-1 -(sec-butyl)-N-((4,6- dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-3-methyl-1 H-indole-4-carboxamide (100 mg, 0.225 mmol), 1 -(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (85 mg, 0.293 mmol), 1 ,2-Dimethoxyethane (DME) (3 mL), water (1.000 mL) and sodium carbonate (0.338 mL, 0.675 mmol), and the mixture was degassed for 5 min by bubbling nitrogen. PdCI₂(dppf)-CH₂CI₂ adduct (14.70 mg, 0.018 mmol) was added and the tube was sealed. The mixture was irradiated (microwave) at 140 °C for 10 min. The mixture was concentrated and the residue was taken up into MeOH and filtered. The filtrate was purified using reverse-phase HPLC (eluent: 25%ACN/H₂0, 0.1 % NH₄OH to 60%

ACN/H₂0, 0.1 % NH₄OH ) to give 91 mg of product as off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.70 – 0.78 (m, 3H), 1.37 – 1.44 (m, 3H), 1 .75 – 1.87 (m, 2H), 2.1 1 (s, 3H), 2.16 (s, 3H), 2.22 – 2.27 (m, 3H), 2.77 – 2.85 (m, 4H), 3.41 – 3.49 (m, 4H), 4.35 (d, J=5.31 Hz, 2H), 4.56 – 4.68 (m, 1 H), 5.87 (s, 1 H), 6.88 (d, J=8.84 Hz, 1 H), 7.17 (d, J=1.52 Hz, 1 H), 7.26 (s, 1 H), 7.73 (d, J=1.26 Hz, 1 H), 7.91 (dd, J=8.84, 2.53 Hz, 1 H), 8.16 (t, J=5.05 Hz, 1 H), 8.50 (d, J=2.53 Hz, 1 H); LCMS: 527.8 (MH+).

Example 271

A/-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-3-methyl-1 -[(1 /?)-1-methylpropyl]- 6-[6-(1 -piperazinyl)-3-pyridinyl]-1 -indole-4-carboxamide

To a 30 mL microwave vial were added (R)-6-bromo-1-(sec-butyl)-N-((4,6- dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-3-methyl-1 H-indole-4-carboxamide (100 mg, 0.225 mmol), 1 -(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (85 mg, 0.293 mmol), 1 ,2-Dimethoxyethane (DME) (3 mL), water (1.000 mL) and sodium carbonate (0.338 mL, 0.675 mmol), and the mixture was degassed for 5 min by bubbling nitrogen. PdCI₂(dppf)-CH₂Cl2 adduct (14.70 mg, 0.018 mmol) was added and the tube was sealed. The mixture was irradiated (microwave) at 140 °C for 10 min. The mixture was concentrated and the residue was taken up into MeOH and filtered. The filtrate was purified using reverse-phase HPLC (eluent: 25%ACN/H₂0, 0.1 % NH₄OH to 60%

ACN/H₂0, 0.1 % NH₄OH ) to give 90 mg of product as off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.73 (m, 3H), 1.41 (d, J=6.57 Hz, 3H), 1.81 (td, J=7.14, 2.91 Hz, 2H), 2.1 1 (s, 3H), 2.15 – 2.20 (m, 3H), 2.24 (s, 3H), 2.77 – 2.83 (m, 4H), 3.41 – 3.49 (m, 4H), 4.35 (d, J=5.05 Hz, 2H), 4.54 – 4.68 (m, 1 H), 5.87 (s, 1 H), 6.88 (d, J=8.84 Hz, 1 H), 7.17 (d, J=1.52 Hz, 1 H), 7.26 (s, 1 H), 7.73 (d, J=1.26 Hz, 1 H), 7.91 (dd, J=8.84, 2.53 Hz, 1 H), 8.16 (t, J=5.05 Hz, 1 H), 8.50 (d, J=2.27 Hz, 1 H); LCMS: 527.7 (MH+)

PATENT

WO 2011140324

Example 270

N-[(4,6-dimethyl-2-oxo-l,2-dihydro-3-pyridinyl)methyl]-3-methyl-l-[(15)-l-methylpropyl]-6-[6-(l-piperazinyl)-3-pyridinyl]-lH-indole-4-carboxamide

To a 30 niL microwave vial were added (S)-6-bromo-l-(sec-butyl)-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3 -methyl- lH-indole-4-carboxamide (100 mg, 0.225 mmol), l-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (85 mg, 0.293 mmol), 1 ,2-Dimethoxyethane (DME) (3 mL), water (1.000 mL) and sodium carbonate (0.338 mL, 0.675 mmol), and the mixture was degassed for 5 min by bubbling nitrogen. PdCi₂(dppf)-CH₂Ci₂ adduct (14.70 mg, 0.018 mmol) was added and the tube was sealed. The mixture was irradiated (microwave) at 140 °C for 10 min. The mixture was concentrated and the residue was taken up into MeOH and filtered. The filtrate was purified using reverse-phase HPLC (eluent: 25%ACN/H₂0, 0.1% NH₄OH to 60% ACN/H₂0, 0.1% NH₄OH ) to give 91 mg of product as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.70 – 0.78 (m, 3H), 1.37 – 1.44 (m, 3H), 1.75 – 1.87 (m, 2H), 2.11 (s, 3H), 2.16 (s, 3H), 2.22 – 2.27 (m, 3H), 2.77 – 2.85 (m, 4H), 3.41 – 3.49 (m, 4H), 4.35 (d, J=5.31 Hz, 2H), 4.56 – 4.68 (m, IH), 5.87 (s, IH), 6.88 (d, J=8.84 Hz, IH), 7.17 (d, J=1.52 Hz, IH), 7.26 (s, IH), 7.73 (d, J=1.26 Hz, IH), 7.91 (dd, J=8.84, 2.53 Hz, IH), 8.16 (t, J=5.05 Hz, IH), 8.50 (d, J=2.53 Hz, IH); LCMS: 527.8 (MH+).

Example 271

N-[(4,6-dimethyl-2-oxo-l,2-dihydro-3-pyridinyl)methyl]-3-methyl-l-[(li?)-l-methylpropyl]-6-[6-(l-piperazinyl)-3-pyridinyl]-l -indole-4-carboxamide

To a 30 mL microwave vial were added (R)-6-bromo-l-(sec-butyl)-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3 -methyl- lH-indole-4-carboxamide (100 mg, 0.225 mmol), l-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (85 mg, 0.293 mmol), 1 ,2-Dimethoxyethane (DME) (3 mL), water (1.000 mL) and sodium carbonate (0.338 mL, 0.675 mmol), and the mixture was degassed for 5 min by bubbling nitrogen. PdCl₂(dppf)-CH₂Cl₂ adduct (14.70 mg, 0.018 mmol) was added and the tube was sealed. The mixture was irradiated (microwave) at 140 °C for 10 min. The mixture was concentrated and the residue was taken up into MeOH and filtered. The filtrate was purified using reverse-phase HPLC (eluent: 25%ACN/H₂0, 0.1% NH₄OH to 60% ACN/H₂0, 0.1% NH₄OH ) to give 90 mg of product as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.73 (m, 3H), 1.41 (d, J=6.57 Hz, 3H), 1.81 (td, J=7.14, 2.91 Hz, 2H), 2.11 (s, 3H), 2.15 – 2.20 (m, 3H), 2.24 (s, 3H), 2.77 – 2.83 (m, 4H), 3.41 – 3.49 (m, 4H), 4.35 (d, J=5.05 Hz, 2H), 4.54 -4.68 (m, 1H), 5.87 (s, 1H), 6.88 (d, J=8.84 Hz, 1H), 7.17 (d, J=1.52 Hz, 1H), 7.26 (s, 1H), 7.73 (d, J=1.26 Hz, 1H), 7.91 (dd, J=8.84, 2.53 Hz, 1H), 8.16 (t, J=5.05 Hz, 1H), 8.50 (d, J=2.27 Hz, 1H); LCMS: 527.7 (MH+).

REF

Tian X, Zhang S, Liu HM, et al. Histone lysine-specific methyltransferases and demethylases in carcinogenesis: new targets for cancer therapy and prevention. Curr Cancer Drug Targets. 2013 Jun 10;13(5):558-79. PMID: 23713993.

McCabe MT, Ott HM, Ganji G, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012 Dec 6;492(7427):108-12. PMID: 23051747.

WO2005034845A2 *	Jul 13, 2004	Apr 21, 2005	Supergen, Inc.	Compositions and methods for treatment of cancer
WO2007053114A1 *	Oct 30, 2006	May 10, 2007	S*Bio Pte Ltd	Method of predicting a response to hdac inhibitors
WO2010090723A2 *	Feb 2, 2010	Aug 12, 2010	University Of Georgia Research Foundation, Inc.	Methods of inhibiting fibrogenesis and treating fibrotic disease
US20110035336	May 1, 2008	Feb 10, 2011	Yigang Cai	Rating change for a prepaid session based on movement of a mobile device
US20110035340	Aug 7, 2009	Feb 10, 2011	Fibre-Craft Materials Corp.	Decorating system and method of marketing and enhancing a surface area using a decorating system
US20110035344	Aug 6, 2009	Feb 10, 2011	International Business Machines Corporation	Computing mixed-integer program solutions using multiple starting vectors
US20110064664 *	Oct 8, 2008	Mar 17, 2011	The Board Of Regents Of The University Of Texas System	Methods and compositions involving chitosan nanoparticles

WO2015077194A1 *	Nov 18, 2014	May 28, 2015	Bristol-Myers Squibb Company	Inhibitors of lysine methyl transferase
WO2015132765A1 *	Mar 6, 2015	Sep 11, 2015	Glaxosmithkline Intellectual Property (No.2) Limited	Enhancer of zeste homolog 2 inhibitors
WO2015141616A1 *	Mar 16, 2015	Sep 24, 2015	第一三共株式会社	1,3-benzodioxole derivative
WO2016066697A1 *	Oct 28, 2015	May 6, 2016	Glaxosmithkline Intellectual Property (No.2) Limited	Enhancer of zeste homolog 2 inhibitors
US9051269	Nov 19, 2012	Jun 9, 2015	Constellation Pharmaceuticals, Inc.	Modulators of methyl modifying enzymes, compositions and uses thereof
US9085583	Feb 11, 2013	Jul 21, 2015	Constellation—Pharmaceuticals, Inc.	Modulators of methyl modifying enzymes, compositions and uses thereof
US20150344459 *	Dec 20, 2013	Dec 3, 2015	Epizyme, Inc.	1,4-pyridone bicyclic heteroaryl compounds

/////////GSK-2816126, GSK-126, 2816126, 1346574-57-9, GSK 126, GSK 126, GSK 2816126, GSK 2816126A

CC=5C=C(C)NC(=O)C=5CNC(=O)c1cc(cc2c1c(C)cn2[C@@H](C)CC)c3cnc(cc3)N4CCNCC4

GSK-2838232

June 13, 2016 7:40 am / 1 Comment on GSK-2838232

GSK-2838232

4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((3-chlorobenzyl)(2-(dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.

28-Norlup-18-en-21-one, 3-(3-carboxy-3-methyl-1-oxobutoxy)-17-[(1R)-2-[[(4-chlorophenyl)methyl][2-(dimethylamino)ethyl]amino]-1-hydroxyethyl]-, (3β)-

Glaxosmithkline Llc INNOVATOR

Mark Andrew HATCHER, Brian Alvin Johns,Michael Tolar Martin, Elie Amine TABET, Jun Tang

A reverse transcriptase inhibitor potentially for the treatment of HIV infection.

GSK-2838232; GSK-8232; 2838232

CAS No. 1443460-91-0

C48H73ClN2O6,809.56

SYNTHESIS

PART 1

PART2

PART3

PART 4

AND UNWANTEDISOMER SHOWN BELOW

PART5

GSK2838232 is a novel human immune virus (HIV) maturation inhibitor being developed for the treatment of chronic HIV infection. GSK2838232 is a betulin derivative

Human immunodeficiency virus type 1 (HIV-1 ) leads to the contraction of acquired immune deficiency disease (AIDS). The number of cases of HIV continues to rise, and currently over twenty-five million individuals worldwide suffer from the virus. Presently, long-term suppression of viral replication with antiretroviral drugs is the only option for treating HIV-1 infection. Indeed, the U.S. Food and Drug Administration has approved twenty-five drugs over six different inhibitor classes, which have been shown to greatly increase patient survival and quality of life.

However, additional therapies are still required because of undesirable drug-drug interactions; drug-food interactions; non-adherence to therapy; and drug resistance due to mutation of the enzyme target.

Currently, almost all HIV positive patients are treated with therapeutic regimens of antiretroviral drug combinations termed, highly active antiretroviral therapy (“HAART”). However, HAART therapies are often complex because a combination of different drugs must be administered often daily to the patient to avoid the rapid emergence of drug-resistant HIV-1 variants. Despite the positive impact of HAART on patient survival, drug resistance can still occur. The emergence of multidrug-resistant HIV-1 isolates has serious clinical consequences and must be suppressed with a new drug regimen, known as salvage therapy.

Current guidelines recommend that salvage therapy includes at least two, and preferably three, fully active drugs. Typically, first-line therapies combine three to four drugs targeting the viral enzymes reverse transcriptase and protease. One option for salvage therapy is to administer different combinations of drugs from the same mechanistic class that remain active against the resistant isolates.

However, the options for this approach are often limited, as resistant mutations frequently confer broad cross-resistance to different drugs in the same class.

Alternative therapeutic strategies have recently become available with the development of fusion, entry, and integrase inhibitors. However, resistance to all three new drug classes has already been reported both in the lab and in patients. Sustained successful treatment of HIV-1 -infected patients with antiretroviral drugs will therefore require the continued development of new and improved drugs with new targets and mechanisms of action.

Presently, long-term suppression of viral replication with antiretroviral drugs is the only option for treating HIV-1 infection. To date, a number of approved drugs have been shown to greatly increase patient survival. However, therapeutic regimens known as highly active antiretroviral therapy (HAART) are often complex because a combination of different drugs must be administered to the patient to avoid the rapid emergence of drug-resistant HIV-1 variants. Despite the positive impact of HAART on patient survival, drug resistance can still occur.

The HIV Gag polyprotein precursor (Pr55Gag), which is composed of four protein domains – matrix (MA), capsid (CA), nucleocapsid (NC) and p6 – and two spacer peptides, SP1 and SP2, represents a new therapeutic target. Although the cleavage of the Gag polyprotein plays a central role in the progression of infectious virus particle production, to date, no antiretroviral drug has been approved for this mechanism.

In most cell types, assembly occurs at the plasma membrane, and the

MA domain of Gag mediates membrane binding. Assembly is completed by budding of the immature particle from the cell. Concomitant with particle release, the virally encoded PR cleaves Gag into the four mature protein domains, MA, CA, NC and p6, and the two spacer peptides, SP1 and SP2. Gag-Pol is also cleaved by PR, liberating the viral enzymes PR, RT and IN. Gag proteolytic processing induces a

morphological rearrangement within the particle, known as maturation. Maturation converts the immature, donut-shaped particle to the mature virion, which contains a condensed conical core composed of a CA shell surrounding the viral RNA genome in a complex with NC and the viral enzymes RT and IN. Maturation prepares the virus for infection of a new cell and is absolutely essential for particle infectivity.

Bevirimat (PA-457) is a maturation inhibitor that inhibits the final step in the processing of Gag, the conversion of capsid-SP1 (p25) to capsid, which is required for the formation of infectious viral particles. Bevirimat has activity against ART-resistant and wild-type HIV, and has shown synergy with antiretrovirals from all classes. Bevirimat reduced HIV viral load by a mean of 1.3 logi₀/mL in patients who achieved trough levels of >= 20 μg/mL and who did not have any of the key baseline Gag polymorphisms at Q369, V370 or T371. However, Bevirimat users with Gag polymorphisms at Q369, V370 or T371 demonstrated significantly lower load reductions than patients without Gag polymorphisms at these sites.

Other examples of maturation inhibitors can be found in PCT Patent

Application No. WO201 1/100308, “Derivatives of Betulin”; PCT Patent Application No. PCT/US2012/024288, “Novel Anti-HIV Compounds and Methods of Use Thereof ; Chinese PCT Application No. PCT/CN201 1/001302, “Carbonyl Derivatives of Betulin”; Chinese PCT Application No. PCT/CN201 1/001303, “Methylene Derivatives of Betulin”; Chinese PCT Application Nos. PCT/CN201 1/002105 and PCT/CN201 1/002159, “Propenoate Derivatives of Betulin”. Maturation inhibitors in the prior art leave open gaps in the areas of polymorphism coverage whereby potency against a broad range of clinically relevant gag sequences is extremely important, along with overall potency including the clinically relevant protein adjusted antiviral activity that will be required for robust efficacy in long term durability trials. To date, no maturation inhibitor has achieved an optimal balance of these properties.

PATENT

WO 2013090664

https://www.google.com/patents/WO2013090664A1?cl=en

Example 17: Compound 50

4-(((3aR, 5aR, 5bR, 7aR, 9S, 11aR, 11bR, 13aS)-3a-((S)-1-Acetoxy-2-((4- chlorobenzyl)amino)ethyl)-1-isopropyl-5a, 5b, 8, 8, 11 a-pentamethyl-2-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,9, 10, 11, 11a, 11b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid

[00241] The title compound was made in a similar manner to Example 16 and isolated as a TFA salt. ¹H NMR (400MHz ,CHLOROFORM-d) δ = 7.49 – 7.30 (m, 4 H), 5.85 – 5.71 (m, 1 H), 4.59 – 4.40 (m, 1 H), 4.31 – 4.03 (m, 2 H), 3.41 – 2.79 (m, 4 H), 2.79 – 2.50 (m, 2 H), 2.37 (d, J = 18.1 Hz, 2 H), 2.02 – 0.63 (m, 49 H); LC/MS: m/z calculated 779.5, found 780.3 (M+1 )⁺.

Example 18: Compound 51

4-(((3aR, 5aR, 5bR, 7aR, 9S, 11aR, 11bR, 13aS)-3a-((R)-2-((4-Chlorobenzyl)(2- (dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8, 11a-pe

2-0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,9, 10, 11, 11a, 11b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid

[00242] To a solution of 2-(dimethylamino)acetaldehyde, hydrochloride (6.75 g, 54.6 mmol) in methanol (20 ml_) was added 4-

(((3aR,5aR,5bR,7aR,9S, 1 1 aR, 1 1 bR, 13aS)-3a-((R)-2-((4-chlorobenzyl)amino)-1 – hydroxyethyl)-1 -isopropyl-5a,5b,8,8, 1 1 a-pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,1 1 ,1 1 a,1 1 b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid , Trifluoroacetic acid salt (46) (9.5 g, 10.92 mmol). The pH was adjusted to 7-8 with Et₃N. The reaction mixture was stirred at rt for 2 h. Sodium cyanoborohydride (0.686 g, 10.92 mmol) was then added and the mixture was stirred at rt overnight. After the reaction was complete, water (15 ml_) and EtOAc (15 ml_) were added, and then the organic phase was removed and concentrated under reduced presure. The product was extracted with EtOAc (80 ml_x3), the combined organic phase was washed with brine, dried, and concentrated. The product was purified by flash chromatography (DCM:EtOAc=2: 1 to 1 : 1 , then DCM:MeOH=100: 1 to 20: 1 ) to give 4- (((3aR,5aR,5bR,7aR,9S, 1 1 aR, 1 1 bR, 13aS)-3a-((R)-2-((4-chlorobenzyl)(2- (dimethylamino)ethyl)amino)-1 -hydroxyethyl)-1 -isopropyl-5a,5b,8,8, 1 1 a-pentamethyl- 2-0X0-3, 3a,4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1 , 1 1 a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (51 ) (6 g, 7.41 mmol, 67.9 % yield) as white solid. Multiple batches of this material (were combined 95 g), dissolved in 600 mL of dichloromethane and washed with NaHC0₃ (400 ml_*3) and the organic phase was dried over Na₂S0₄, filtered and concentrated. The solids were washed with a mixture of EtOAc: petroleum ether (600 mL), and filtered followed by lyophilization to provide the final title compound 62 g as a white solid. ¹H NMR (400MHz ,METHANOL-d₄) δ = 7.47 – 7.29 (m, 4 H), 4.48 (dd, J = 5.8, 10.3 Hz, 1 H), 4.15 – 4.04 (m, 1 H), 3.80 (d, J = 13.8 Hz, 1 H), 3.57 (d, J = 14.1 Hz, 1 H), 3.21 – 2.82 (m, 5 H), 2.72 – 2.41 (m, 9 H), 2.37 – 2.05 (m, 4 H), 2.05 – 0.74 (m, 45 H);

LC/MS: m/z calculated 808.5, found 809.5 (M+1 )⁺.

REFERENCES

Hatcher, Mark Andrew; Johns, Brian Alvin; Martin, Michael Tolar; Tabet, Elie Amine; Tang, Jun. Preparation of betulin derivatives for the treatment of HIV, PCT Int. Appl. (2013), WO 2013090664 A1 20130620.

////////GSK-2838232, 1443460-91-0, GSK 2838232, GSK-8232, 2838232, treatment of HIV, phase1

O=C(C1)C(C(C)C)=C2[C@@]1([C@@H](O)CN(CCN(C)C)CC3=CC=CC(Cl)=C3)CC[C@]4(C)[C@]2([H])CC[C@@]5([H])[C@@]4(C)CC[C@]6([H])[C@]5(C)CC[C@H](OC(CC(C)(C)C(O)=O)=O)C6(C)C

TD 1607

June 13, 2016 5:04 am / Leave a comment

TD-1607

A glycopeptide-cephalosporin heterodimer potentially for the treatment of gram-positive bacterial infection.

CAS No. 827040-07-3

C₉₅ H₁₀₉ Cl₃ N₁₈ O₃₁ S_2,

Molecular Weight, 2169.47

Vancomycin, 29-[[[2-[[6-[[[1-[[(6R,7R)-7-[[(2Z)-2-(2-amino-5-chloro-4-thiazolyl)-2-(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]pyridinium-4-yl]methyl]amino]-1,6-dioxohexyl]amino]ethyl]amino]methyl]-, inner salt

Vancomycin, 29-[[[2-[[6-[[[1-[[(6R,7R)-7-[[(2Z)-(2-amino-5-chloro-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]pyridinium-4-yl]methyl]amino]-1,6-dioxohexyl]amino]ethyl]amino]methyl]-, inner salt

Originator Theravance
Developer Theravance Biopharma
Class Antibacterials; Cephalosporins; Glycopeptides
Mechanism of Action Cell wall inhibitors
- Phase I Gram-positive infections
Most Recent Events
- 21 Apr 2016 Phase I development is ongoing in USA
- 01 Jul 2014 Theravance completes a phase I trial in Healthy volunteers in in USA (NCT01949103)
- 02 Jun 2014 Theravance Biopharma is formed as a spin-off of Theravance
- Company Theravance Biopharma Inc.
  
  Description Glycopeptide cephalosporin heterodimer antibiotic
  
  Molecular Target
  
  Mechanism of Action
  
  Therapeutic Modality Small molecule: Combination
  
  Latest Stage of Development Phase I
  
  Standard Indication Gram-negative bacterial infection
  
  Indication Details Treat Gram-positive bacterial infections

PATENT

WO 2005005436

https://www.google.com/patents/WO2005005436A2?cl=en29

The present invention provides novel cross-linked glycopeptide – cephalosporin compounds that are useful as antibiotics. The compounds of this invention have a unique chemical structure in which a glycopeptide group is covalently linked to a pyridinium moiety of a cephalosporin group. Among other properties, compounds of this invention have been found to possess surprising and unexpected potency against Gram-positive bacteria including methicillin-resistant Staphylococci aureus (MRSA). Accordingly, in one aspect, the invention provides a compound of formula I:

////////Theravance Biopharma, TD 1607, phase 1, glycopeptide-cephalosporin heterodimer , gram-positive bacterial infection

Temanogrel

June 13, 2016 4:08 am / 9 Comments on Temanogrel

ChemSpider 2D Image | temanogrel | C24H28N4O4

Temanogrel

APD 791

3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholinoethoxy)phenyl]benzamide

Benzamide,3-methoxy-N-[3-(1-methyl-1H-pyrazol-5-yl)-4-[2-(4-morpholinyl)ethoxy]phenyl]-

UNII:F42Z27575A

TEMANOGREL; APD791; CHEMBL1084617; UNII-F42Z27575A; 887936-68-7; 3-Methoxy-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide;
Molecular Formula:	C₂₄H₂₈N₄O₄
Molecular Weight:	436.50352 g/mol

Originator Arena Pharmaceuticals
Developer Arena Pharmaceuticals; Ildong Pharmaceutical
Class Antithrombotics; Small molecules
Mechanism of Action Serotonin 2A receptor inverse agonists

Phase I Arterial thrombosis

Most Recent Events

30 Mar 2016 Arena Pharmaceuticals has patents pending for Temanogrel in 12 regions, including Brazil (Arena Pharmaceuticals 10-K; march 2016)
30 Mar 2016 Arena Pharmaceuticals has patent protection for Temanogrel in 87 regions, including USA, Japan, China, Germany, France, Italy, the United Kingdom, Spain, Canada, Russia, India, Australia and South Korea
01 Mar 2015 Ildong Pharmaceutical initiates enrolment in a phase I trial for Arterial thrombosis in South Korea (NCT02419820)

A 5-HT2A inverse agonist potentially for the reduction of the risk of arterial thrombosis.

APD-791

CAS No. 887936-68-7

ChemSpider 2D Image | Temanogrel hydrochloride | C24H29ClN4O4

Temanogrel hydrochloride

Molecular FormulaC₂₄H₂₉ClN₄O₄
Average mass472.965

957466-27-2 CAS

Benzamide, 3-methoxy-N-[3-(1-methyl-1H-pyrazol-5-yl)-4-[2-(4-morpholinyl)ethoxy]phenyl]-, hydrochloride (1:1) [ACD/Index Name]

Temanogrel hydrochloride [USAN]

UNII:5QEY8NZP3T

Temanogrel, also known as APD791, is a highly selective 5-hydroxytryptamine2A receptor inverse agonist under development for the treatment of arterial thrombosis. APD791 displayed high-affinity binding to membranes (K(i) = 4.9 nM) and functional inverse agonism of inositol phosphate accumulation (IC(50) = 5.2 nM) in human embryonic kidney cells stably expressing the human 5-HT(2A) receptor. APD791 was greater than 2000-fold selective for the 5-HT(2A) receptor versus 5-HT(2C) and 5-HT(2B) receptors. APD791 inhibited 5-HT-mediated amplification of ADP-stimulated human and dog platelet aggregation (IC(50) = 8.7 and 23.1 nM, respectively)

Arterial thrombosis is the formation of a blood clot or thrombus inside an artery or arteriole that restricts or blocks the flow of blood and, depending upon location, can result in acute coronary syndrome or stroke. The formation of a thrombus is usually initiated by blood vessel injury, which triggers platelet aggregation and adhesion of platelets to the vessel wall. Treatments aimed at inhibiting platelet aggregation have demonstrated clear clinical benefits in the setting of acute coronary syndrome and stroke. Current antiplatelet therapies include aspirin, which irreversibly inhibits cyclooxygenase (COXa

Abbreviations: COX, cyclooxygenase; ADP, adenosine diphosphate; SAR, structure−activity relationship; hERG, human ether-a-go-go-related gene; CNS, central nervous system; 5-HT, serotonin; AUC, area under the plasma concentration time curve, iv, intravenous; IP, inositol phosphate.

) and results in reduced thromboxane production, clopidogrel and prasugrel, which inhibit platelet adenosine diphosphate (ADP) P₂Y₁₂ receptors, and platelet glycoprotein IIb/IIIa receptor antagonists. Another class of antiplatelet drugs, protease-activated thrombin receptor (PAR-1) antagonists, are also being evaluated in the clinic for the treatment of acute coronary syndrome. The most advanced candidate in this class, N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-{2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-1-methyl-3-oxoperhydro-naphtho[2,3-c]furan-6-yl]-carbamic acid ethyl ester (SCH-530348), is currently in phase 3 trials for the prevention of arterial thrombosis.

The 5-HT_2A receptor is one of 15 different serotonin receptor subtypes.

In the cardiovascular system, modulation of 5-HT_2A receptors on vascular smooth muscle cells and platelets is thought to play an important role in the regulation of cardiovascular function. Platelets are activated by a variety of agonists such as ADP, thrombin, thromboxane, serotonin, epinephrine, and collagen. Upon platelet activation at the site of blood vessel injury, a number of factors including serotonin (5-HT) are released. Although by itself serotonin is a weak activator of platelet aggregation, in vitro it can amplify aggregation induced by other agonists as mentioned above. Therefore, serotonin released from activated platelets may induce further platelet aggregation and enhance thrombosis.

The 5-HT_2A receptor antagonist ketanserin was shown in clinical studies to reduce early restenosis(7) and decrease myocardial ischemia during coronary balloon angioplasty.(8)However, in another study, ketanserin did not significantly improve clinical outcomes, and the rate of adverse events was higher than that observed in the control group.(9) Some of the adverse events reported in the latter study could be specific to ketanserin and resulted from its lack of 5-HT_2A receptor selectivity. Other 5-HT_2A antagonists with improved selectivity profiles have shown promise in clinical studies. For example, sarpogrelate was shown to inhibit restenosis following coronary stenting.

Figure 1. Serotonin and known 5-HT_2A receptor antagonists.

Because the 5-HT_2A receptor is expressed both in peripheral tissues and in the central nervous system (CNS), compounds with limited CNS partitioning would be preferred to maximize cardiovascular and blood platelet pharmacological activity while minimizing CNS effects. In addition, because 5-HT_2A receptor inverse agonists are thought to reduce thrombus formation via inhibition of serotonin-mediated amplification of platelet aggregation without inhibiting agonist driven aggregation per se, it is possible that this class of inhibitors will have an improved bleeding risk side effect profile compared to what has been observed with other classes of antithrombotic drugs.

SYNTHESIS

PAPER

Journal of Medicinal Chemistry (2010), 53(11), 4412-4421.

http://pubs.acs.org/doi/abs/10.1021/jm100044a

Serotonin, which is stored in platelets and is released during thrombosis, activates platelets via the 5-HT_2A receptor. 5-HT_2A receptor inverse agonists thus represent a potential new class of antithrombotic agents. Our medicinal program began with known compounds that displayed binding affinity for the recombinant 5-HT_2A receptor, but which had poor activity when tested in human plasma platelet inhibition assays. We herein describe a series of phenyl pyrazole inverse agonists optimized for selectivity, aqueous solubility, antiplatelet activity, low hERG activity, and good pharmacokinetic properties, resulting in the discovery of 10k (APD791). 10k inhibited serotonin-amplified human platelet aggregation with an IC₅₀ = 8.7 nM and had negligible binding affinity for the closely related 5-HT_2B and 5-HT_2C receptors. 10k was orally bioavailable in rats, dogs, and monkeys and had an acceptable safety profile. As a result, 10k was selected further evaluation and advanced into clinical development as a potential treatment for arterial

Discovery and Structure−Activity Relationship of 3-Methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide (APD791): A Highly Selective 5-Hydroxytryptamine_2A Receptor Inverse Agonist for the Treatment of Arterial Thrombosis

Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, California 92121

J. Med. Chem., 2010, 53 (11), pp 4412–4421

DOI: 10.1021/jm100044a

Publication Date (Web): May 10, 2010

*To whom correspondence should be addressed. Phone: +1 858-453-7200. Fax: +1 858-453-7210. E-mail:yxiong@arenapharm.com.

3-Methoxy-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide (10k)

10k was prepared in a manner similar to that described for 10c, using 9d (120 mg, 0.40 mmol) and 3-methoxybenzoyl chloride (81 mg, 0.48 mmol) to give the TFA salt of 10k as a white solid (88 mg, 51%); mp (HCl salt, recrystallized from iPrOH) 214−216 °C. ¹H NMR (acetone-d₆, 400 MHz) δ: 2.99−3.21 (m, 2H), 3.22−3.45 (m, 2H), 3.66 (t, J = 4.8 Hz, 2H), 3.75 (s, 3H), 3.85 (s, 3H), 3.79−3.89 (m, 4H), 4.58 (t, J = 4.8 Hz, 2H), 6.29 (d, J = 2.0 Hz, 1H), 7.13 (dd, J = 2.5, 8.3 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.47 (d, J = 1.7 Hz, 1H), 7.52 (t, J = 1.7 Hz, 1H), 7.56 (d, J = 7.0 Hz, 1H), 7.80−7.83 (m, 1H), 7.91−7.96 (m, 1H), 9.54 (s, 1H). LCMSm/z = 437.5 [M + H]⁺.

Additional Information

Oral administration of APD791 to dogs resulted in acute (1-h) and subchronic (10-day) inhibition of 5-HT-mediated amplification of collagen-stimulated platelet aggregation in whole blood. Two active metabolites, APD791-M1 and APD791-M2, were generated upon incubation of APD791 with human liver microsomes and were also indentified in dogs after oral administration of APD791. The affinity and selectivity profiles of both metabolites were similar to APD791. These results demonstrate that APD791 is an orally available, high-affinity 5-HT(2A) receptor antagonist with potent activity on platelets and vascular smooth muscle.(http://www.ncbi.nlm.nih.gov/pubmed/19628629).

PATENT

WO 2006055734

https://google.com/patents/WO2006055734A2?cl=en

Example 1.88: Preparation of 3-methoxy-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin~

4-yl-ethoxy)-phenyl]-benzamide (Compound 733).

A mixture of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (120 mg, 0.40 mmole), 3-methoxy-benzoyl chloride (81 mg, 0.48 mmole), and triethylamine (0.1 mL, 0.79 mmole) in 5 mL THF was stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give the title compound as a white solid (TFA salt, 88 mg, 51 %). ¹H NMR ( Acetone-^, 400 MHz) 2.99-3.21 (m, 2H), 3.22-3.45 (m, 2H), 3.66 (t, J= 4.80 Hz, 2H), 3.75 (s, 3H), 3.85 (s, 3H), 3.79-3.89 (m, 4H), 4.58 (t, J= 4.80 Hz, 2H), 6.29 (d, J= 2.02 Hz IH), 7.13 (dd, J= 8.34, 2.53 Hz, IH), 7.22 (d, J= 8.84 Hz, IH), 7.42 (t, J= 7.83 Hz, IH), 7.47 (d, J= 1.77 Hz, IH), 7.52 (t, J= 1.77 Hz, IH), 7.56 (d, J= 7.07 Hz, IH), 7.80-7.83 (m, IH), 7.91-7.96 (m, IH), 9.54 (s, NH). Exact mass calculated for C₂₄H₂₈N₄O₄ 436.2, found 437.5 (MH⁺).

References

1: Xiong Y, Teegarden BR, Choi JS, Strah-Pleynet S, Decaire M, Jayakumar H, Dosa
PI, Casper MD, Pham L, Feichtinger K, Ullman B, Adams J, Yuskin D, Frazer J,
Morgan M, Sadeque A, Chen W, Webb RR, Connolly DT, Semple G, Al-Shamma H.
Discovery and structure-activity relationship of
3-methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide
(APD791): a highly selective 5-hydroxytryptamine2A receptor inverse agonist for
the treatment of arterial thrombosis. J Med Chem. 2010 Jun 10;53(11):4412-21.
doi: 10.1021/jm100044a. PubMed PMID: 20455563.

2: Przyklenk K, Frelinger AL 3rd, Linden MD, Whittaker P, Li Y, Barnard MR, Adams
J, Morgan M, Al-Shamma H, Michelson AD. Targeted inhibition of the serotonin
5HT2A receptor improves coronary patency in an in vivo model of recurrent
thrombosis. J Thromb Haemost. 2010 Feb;8(2):331-40. doi:
10.1111/j.1538-7836.2009.03693.x. Epub 2009 Nov 17. PubMed PMID: 19922435; PubMed
Central PMCID: PMC2916638.

3: Adams JW, Ramirez J, Shi Y, Thomsen W, Frazer J, Morgan M, Edwards JE, Chen W,
Teegarden BR, Xiong Y, Al-Shamma H, Behan DP, Connolly DT. APD791,
3-methoxy-n-(3-(1-methyl-1h-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide,
a novel 5-hydroxytryptamine 2A receptor antagonist: pharmacological profile,
pharmacokinetics, platelet activity and vascular biology. J Pharmacol Exp Ther.
2009 Oct;331(1):96-103. doi: 10.1124/jpet.109.153189. Epub 2009 Jul 23. PubMed
PMID: 19628629.

Patent ID	Date	Patent Title
US2015361031	2015-12-17	STAT3 INHIBITOR
US8785441	2014-07-22	3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US2013296321	2013-11-07	CRYSTALLINE FORMS AND PROCESSES FOR THE PREPARATION OF PHENYL-PYRAZOLES USEFUL AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR
US2012252813	2012-10-04	CRYSTALLINE FORMS OF CERTAIN 3-PHENYL-PYRAZOLE DERIVATIVES AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO
US8148417	2012-04-03	PRIMARY AMINES AND DERIVATIVES THEREOF AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO
US8148418	2012-04-03	ETHERS, SECONDARY AMINES AND DERIVATIVES THEREOF AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO
US2011105456	2011-05-05	3-PHENYL-PYRAZOLE DERIVATIVES AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO
US7884101	2011-02-08	3-Phenyl-pyrazole derivatives as modulators of the 5-HT2a serotonin receptor useful for the treatment of disorders related thereto
US2010234380	2010-09-16	CRYSTALLINE FORMS AND PROCESSES FOR THE PREPARATION OF PHENYL-PYRAZOLES USEFUL AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR
US2007244086	2007-10-18	3-Phenyl-Pyrazole Derivatives as Modulators of the 5-Ht2A Serotonin Receptor Useful for the Treatment of Disorders Related Thereto

///////////APD-791 , 887936-68-7, Temanogrel , PHASE 1, ARENA,

CN1C(=CC=N1)C2=C(C=CC(=C2)NC(=O)C3=CC(=CC=C3)OC)OCCN4CCOCC4

C(=O)(c1cc(ccc1)OC)Nc1ccc(c(c1)c1n(ncc1)C)OCCN1CCOCC1

Genistein

June 13, 2016 3:45 am / Leave a comment

Genistein

5,7-Dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one; Baichanin A; Bonistein; 4’,5,7-Trihydroxyisoflavone; GeniVida; Genisteol; NSC 36586; Prunetol; Sophoricol;


CAS Number:	446-72-0
	BIO-300; G-2535; PTI-G-4660; SIPI-9764-I; PTIG-4660; SIPI-9764I
Molecular form.:	C₁₅H₁₀O₅
Appearance:	Light Tan to Light Yellow Solid
Melting Point:	>277°C (dec.)
Mol. Weight:	270.24

Genistein , an isoflavone found in many Fabaceae plants and important non-nutritional constituent of soybeans (Glycine max Merill), is a well-known plant metabolite from phenylpropanoid pathway, chiefly because of its presence in numerous phytoestrogenic dietary supplements. In fact, the compound also strives for higher medicinal status, undergoing dozens of clinical trials for various ailments, from osteoporosis to cancer

IR (KBr, cm^–1; inter alia): 3411, 3104, 1651, 1615, 1570, 1519, 1504, 1424, 1361, 1309, 1202, 1179, 1145, 1043, 911, 840, 790.

¹H NMR (200 MHz, THF-d8), δ (ppm): 6.17 (d, J = 2,2 Hz, 1H); 6.26 (d, J = 2,2 Hz, 1H); 6.78 (m, 2H); 7.41 (m, 2H); 8.02 (s, 1H); 8.50 (bs, 1H); 9.34 (bs, 1H); 13.02 (s, 1H).

¹³C NMR (THF-d₈), δ (ppm): 94.13; 99.73; 106.20; 115.82; 122.95; 124.17; 130.84; 153.78; 158.73; 159.08; 164.24; 165.16; 181.46.

An EGFR/DNA topoisomerase II inhibitor potentially for the treatment of bladder cancer and prostate cancer.

NMR

Genistein; CAS: 446-72-0

REF http://www.wangfei.ac.cn/nmrspectra/7/1/30

SEE https://www.google.com/patents/EP2373326A1?cl=en

Genistein is an angiogenesis inhibitor and a phytoestrogen and belongs to the category of isoflavones. Genistein was first isolated in 1899 from the dyer’s broom, Genista tinctoria; hence, the chemical name. The compound structure was established in 1926, when it was found to be identical with prunetol. It was chemically synthesized in 1928.^[1]

Natural occurrences

Isoflavones such as genistein and daidzein are found in a number of plants including lupin, fava beans, soybeans, kudzu, andpsoralea being the primary food source,^[2]^[3] also in the medicinal plants, Flemingia vestita^[4] and F. macrophylla,^[5]^[6] and coffee.^[7] It can also be found in Maackia amurensis cell cultures.^[8]

Extraction and purification

Most of the isoflavones in plants are present in a glycosylated form. The unglycosylated aglycones can be obtained through various means such as treatment with the enzyme β-glucosidase, acid treatment of soybeans followed by solvent extraction, or by chemical synthesis.^[9] Acid treatment is a harsh method as concentrated inorganic acids are used. Both enzyme treatment and chemical synthesis are costly. A more economical process consisting of fermentation for in situ production of β-glucosidase to isolate genistein has been recently investigated.^[10]

Biological effects

Besides functioning as antioxidant and anthelmintic, many isoflavones have been shown to interact with animal and human estrogen receptors, causing effects in the body similar to those caused by the hormone estrogen. Isoflavones also produce non-hormonal effects.

Molecular function

Genistein influences multiple biochemical functions in living cells:

full agonist of ERβ (EC₅₀ = 7.62 nM) and, to a much lesser extent (~20-fold), full agonist^[11] or partial agonist of ERα^[12]
agonist of GPER (GPR30)^[13]
activation of peroxisome proliferator-activated receptors (PPARs)
inhibition of several tyrosine kinases
inhibition of topoisomerase
inhibition of AAAD
direct antioxidation with some proxidative features
activation of Nrf2 antioxidative response
stimulation of autophagy^[14]^[15]^[16]
inhibition of the mammalian hexose transporter GLUT1
contraction of several types of smooth muscles
modulation of CFTR channel, potentiating its opening at low concentration and inhibiting it a higher doses.
inhibition of cytosine methylation
inhibition of DNA methyltransferase^[17]
inhibition of the glycine receptor

Activation of PPARs

Isoflavones genistein and daidzein bind to and transactivate all three PPAR isoforms, α, δ, and γ.^[18] For example, membrane-bound PPARγ-binding assay showed that genistein can directly interact with the PPARγ ligand binding domain and has a measurable Ki of 5.7 mM.^[19] Gene reporter assays showed that genistein at concentrations between 1 and 100 uM activated PPARs in a dose dependent way in KS483 mesenchymal progenitor cells, breast cancer MCF-7 cells, T47D cells and MDA-MD-231 cells, murine macrophage-like RAW 264.7 cells, endothelial cells and in Hela cells. Several studies have shown that both ERs and PPARs influenced each other and therefore induce differential effects in a dose-dependent way. The final biological effects of genistein are determined by the balance among these pleiotrophic actions.^[18]^[20]^[21]

Tyrosine kinase inhibitor

The main known activity of genistein is tyrosine kinase inhibitor, mostly of epidermal growth factor receptor (EGFR). Tyrosine kinases are less widespread than their ser/thr counterparts but implicated in almost all cell growth and proliferation signal cascades.

Redox-active — not only antioxidant

Genistein may act as direct antioxidant, similar to many other isoflavones, and thus may alleviate damaging effects of free radicals in tissues.^[22]^[23]

The same molecule of genistein, similar to many other isoflavones, by generation of free radicals poison topoisomerase II, an enzyme important for maintaining DNA stability.^[24]^[25]^[26]

Human cells turn on beneficial, detoxyfying Nrf2 factor in response to genistein insult. This pathway may be responsible for observed health maintaining properities of small doses of genistein.^[27]

Anthelmintic

The root-tuber peel extract of the leguminous plant Felmingia vestita is the traditional anthelmitic of the Khasi tribes of India. While investigating its anthelmintic activity, genistein was found to be the major isoflavone responsible for the deworming property.^[4]^[28] Genistein was subsequently demonstrated to be highly effective against intestinal parasitessuch as the poultry cestode Raillietina echinobothrida,^[28] the pork trematode Fasciolopsis buski,^[29] and the sheep liver fluke Fasciola hepatica.^[30] It exerts its anthelmintic activity by inhibiting the enzymes of glycolysis and glycogenolysis,^[31]^[32] and disturbing the Ca2+ homeostasis and NO activity in the parasites.^[33]^[34] It has also been investigated inhuman tapeworms such as Echinococcus multilocularis and E. granulosus metacestodes that genistein and its derivatives, Rm6423 and Rm6426, are potent cestocides.^[35]

Atherosclerosis

Genistein protects against pro-inflammatory factor-induced vascular endothelial barrier dysfunction and inhibits leukocyte–endothelium interaction, thereby modulating vascular inflammation, a major event in the pathogenesis of atherosclerosis.^[36]

Cancer links

Genistein and other isoflavones have been identified as angiogenesis inhibitors, and found to inhibit the uncontrolled cell growth of cancer, most likely by inhibiting the activity of substances in the body that regulate cell division and cell survival (growth factors). Various studies have found that moderate doses of genistein have inhibitory effects on cancersof the prostate,^[37]^[38] cervix,^[39] brain,^[40] breast^[37]^[41]^[42] and colon.^[16] It has also been shown that genistein makes some cells more sensitive to radio-therapy.;^[43] although, timing of phytoestrogen use is also important. ^[43]

Genistein’s chief method of activity is as a tyrosine kinase inhibitor. Tyrosine kinases are less widespread than their ser/thr counterparts but implicated in almost all cell growth and proliferation signal cascades. Inhibition of DNA topoisomerase II also plays an important role in the cytotoxic activity of genistein.^[25]^[44] Genistein has been used to selectively target pre B-cells via conjugation with an anti-CD19 antibody.^[45]

Studies on rodents have found genistein to be useful in the treatment of leukemia, and that it can be used in combination with certain other antileukemic drugs to improve their efficacy.^[46]

Estrogen receptor — more cancer links

Due to its structure similarity to 17β-estradiol (estrogen), genistein can compete with it and bind to estrogen receptors. However, genistein shows much higher affinity towardestrogen receptor β than toward estrogen receptor α.^[47]

Data from in vitro and in vivo research confirms that genistein can increase rate of growth of some ER expressing breast cancers. Genistein was found to increase the rate of proliferation of estrogen-dependent breast cancer when not cotreated with an estrogen antagonist.^[48]^[49]^[50] It was also found to decrease efficiency of tamoxifen and letrozole – drugs commonly used in breast cancer therapy.^[51]^[52] Genistein was found to inhibit immune response towards cancer cells allowing their survival.^[53]

Effects in males

Isoflavones can act like estrogen, stimulating development and maintenance of female characteristics, or they can block cells from using cousins of estrogen. In vitro studies have shown genistein to induce apoptosis of testicular cells at certain levels, thus raising concerns about effects it could have on male fertility;^[54] however, a recent study found that isoflavones had “no observable effect on endocrine measurements, testicular volume or semen parameters over the study period.” in healthy males given isoflavone supplements daily over a 2-month period.^[55]

Carcinogenic and toxic potential

Genistein was, among other flavonoids, found to be a strong topoisomerase inhibitor, similarly to some chemotherapeutic anticancer drugs ex. etoposide and doxorubicin.^[24]^[56]In high doses it was found to be strongly toxic to normal cells.^[57] This effect may be responsible for both anticarcinogenic and carcinogenic potential of the substance.^[26]^[58] It was found to deteriorate DNA of cultured blood stem cells, what may lead to leukemia.^[59] Genistein among other flavonoids is suspected to increase risk of infant leukemia when consumed during pregnancy.^[60]^[61]

Sanfilippo syndrome treatment

Genistein decreases pathological accumulation of glycosaminoglycans in Sanfilippo syndrome. In vitro animal studies and clinical experiments suggest that the symptoms of the disease may be alleviated by adequate dose of genistein.^[62] Genistein was found to also possess toxic properties toward brain cells.^[57] Among many pathways stimulated by genistein, autophagy may explain the observed efficiency of the substance as autophagy is significantly impaired in the disease.^[63]^[64]

Related compounds

Glycosides

Genistin is the 7-O-beta-D-glucoside of genistein.

Acetylated compounds

Wighteone is the 6-isopentenyl genistein (6-prenyl-5,7,4′-trihydroxyisoflavone)^{[citation needed]}

Pharmaceutical derivatives

KBU2046 under investigation for prostate cancer.^[65]^[66]
B43-genistein, an anti-CD19 antibody linked to genistein e.g. for leukemia.^[67]
Genistein has two known synthesis routes: deoxybenzoin route and chalcone route. Deoxybenzoin route uses friedel-craft reaction, and chalcone route uses aldol condensation as shown in figure 2. Developing synthesis of genistein allows the access to the affordable therapy as well as mass production of commercial genistein supplements. However, it would be recommended to consult with the health care provider and discuss the pros and cons before the use since the effects of genistein on human body are not fully understood yet as discussed above.

Figure 2. Synthesis of genistein via deoxybenzoin route or chalcone route. 10

https://chemprojects263sp11.wikispaces.com/genistein

Paper

Identification of Benzopyran-4-one Derivatives (Isoflavones) as Positive Modulators of GABAA Receptors
ChemMedChem (2011), 6, (8), 1340-1346

http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201100120/abstract

PATENT

By Achmatowicz, Osman et al

From Pol., 204473

References

Walter, E. D. (1941). “Genistin (an Isoflavone Glucoside) and its Aglucone, Genistein, from Soybeans”. Journal of the American Chemical Society 63 (12): 3273–76.doi:10.1021/ja01857a013.
Coward, Lori; Barnes, Neil C.; Setchell, Kenneth D. R.; Barnes, Stephen (1993). “Genistein, daidzein, and their β-glycoside conjugates: Antitumor isoflavones in soybean foods from American and Asian diets”. Journal of Agricultural and Food Chemistry 41 (11): 1961–7. doi:10.1021/jf00035a027.
Jump up^ Kaufman, Peter B.; Duke, James A.; Brielmann, Harry; Boik, John; Hoyt, James E. (1997). “A Comparative Survey of Leguminous Plants as Sources of the Isoflavones, Genistein and Daidzein: Implications for Human Nutrition and Health”. The Journal of Alternative and Complementary Medicine 3 (1): 7–12. doi:10.1089/acm.1997.3.7.PMID 9395689.
^ Jump up to:^a ^b Rao, H. S. P.; Reddy, K. S. (1991). “Isoflavones from Flemingia vestita“. Fitoterapia62 (5): 458.
Jump up^ Rao, K.Nageswara; Srimannarayana, G. (1983). “Fleminone, a flavanone from the stems of Flemingia macrophylla“. Phytochemistry 22 (10): 2287–90. doi:10.1016/S0031-9422(00)80163-6.
Jump up^ Wang, Bor-Sen; Juang, Lih-Jeng; Yang, Jeng-Jer; Chen, Li-Ying; Tai, Huo-Mu; Huang, Ming-Hsing (2012). “Antioxidant and Antityrosinase Activity of Flemingia macrophylla andGlycine tomentella Roots”. Evidence-Based Complementary and Alternative Medicine 2012: 1–7. doi:10.1155/2012/431081. PMID 22997529.
Jump up^ Alves, Rita C.; Almeida, Ivone M. C.; Casal, Susana; Oliveira, M. Beatriz P. P. (2010). “Isoflavones in Coffee: Influence of Species, Roast Degree, and Brewing Method”. Journal of Agricultural and Food Chemistry 58 (5): 3002–7. doi:10.1021/jf9039205.PMID 20131840.
Jump up^ Fedoreyev, S.A; Pokushalova, T.V; Veselova, M.V; Glebko, L.I; Kulesh, N.I; Muzarok, T.I; Seletskaya, L.D; Bulgakov, V.P; Zhuravlev, Yu.N (2000). “Isoflavonoid production by callus cultures of Maackia amurensis”. Fitoterapia 71 (4): 365–72. doi:10.1016/S0367-326X(00)00129-5. PMID 10925005.
Jump up^ Prakash, Om; Saini, Neena; Tanwar, Madan P.; Moriarty, Robert M. (1995). “Hypervalent iodine in organic synthesis: α-functionalization of carbonyl compounds”. Contemporary Organic Synthesis 2 (2): 121–31. doi:10.1039/CO9950200121.
Jump up^ Patravale, VB; Pandit, NT (2011). “Design and optimization of a novel method for extraction of genistein”. Indian Journal of Pharmaceutical Sciences 73 (2): 184–92.doi:10.4103/0250-474x.91583. PMC 3267303. PMID 22303062.
Jump up^ Patisaul, Heather B.; Melby, Melissa; Whitten, Patricia L.; Young, Larry J. (2002). “Genistein Affects ERβ- But Not ERα-Dependent Gene Expression in the Hypothalamus”.Endocrinology 143 (6): 2189–2197. doi:10.1210/endo.143.6.8843. ISSN 0013-7227.
Jump up^ Green, Sarah E (2015), In Vitro Comparison of Estrogenic Activities of Popular Women’s Health Botanicals
Jump up^ Prossnitz, Eric R.; Barton, Matthias (2014). “Estrogen biology: New insights into GPER function and clinical opportunities”. Molecular and Cellular Endocrinology 389 (1-2): 71–83.doi:10.1016/j.mce.2014.02.002. ISSN 0303-7207.
Jump up^ Gossner, G; Choi, M; Tan, L; Fogoros, S; Griffith, K; Kuenker, M; Liu, J (2007). “Genistein-induced apoptosis and autophagocytosis in ovarian cancer cells”. Gynecologic Oncology 105 (1): 23–30. doi:10.1016/j.ygyno.2006.11.009. PMID 17234261.
Jump up^ Singletary, K.; Milner, J. (2008). “Diet, Autophagy, and Cancer: A Review”. Cancer Epidemiology Biomarkers & Prevention 17 (7): 1596–610. doi:10.1158/1055-9965.EPI-07-2917. PMID 18628411.
^ Jump up to:^a ^b Nakamura, Yoshitaka; Yogosawa, Shingo; Izutani, Yasuyuki; Watanabe, Hirotsuna; Otsuji, Eigo; Sakai, Tosiyuki (2009). “A combination of indol-3-carbinol and genistein synergistically induces apoptosis in human colon cancer HT-29 cells by inhibiting Akt phosphorylation and progression of autophagy”. Molecular Cancer 8: 100.doi:10.1186/1476-4598-8-100. PMC 2784428. PMID 19909554.
Jump up^ Fang, Mingzhu; Chen, Dapeng; Yang, Chung S. (January 2007). “Dietary polyphenols may affect DNA methylation”. The Journal of Nutrition 137 (1 Suppl): 223S–228S.PMID 17182830.
^ Jump up to:^a ^b Wang, Limei; Waltenberger, Birgit; Pferschy-Wenzig, Eva-Maria; Blunder, Martina; Liu, Xin; Malainer, Clemens; Blazevic, Tina; Schwaiger, Stefan; Rollinger, Judith M.; Heiss, Elke H.; Schuster, Daniela; Kopp, Brigitte; Bauer, Rudolf; Stuppner, Hermann; Dirsch, Verena M.; Atanasov, Atanas G. (2014). “Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): A review”. Biochemical Pharmacology 92: 73–89. doi:10.1016/j.bcp.2014.07.018. PMC 4212005. PMID 25083916.
Jump up^ Dang, Zhi-Chao; Audinot, Valérie; Papapoulos, Socrates E.; Boutin, Jean A.; Löwik, Clemens W. G. M. (2002). “Peroxisome Proliferator-activated Receptor γ (PPARγ) as a Molecular Target for the Soy Phytoestrogen Genistein”. Journal of Biological Chemistry 278(2): 962–7. doi:10.1074/jbc.M209483200. PMID 12421816.
Jump up^ Dang, Zhi Chao; Lowik, Clemens (2005). “Dose-dependent effects of phytoestrogens on bone”. Trends in Endocrinology and Metabolism 16 (5): 207–13.doi:10.1016/j.tem.2005.05.001. PMID 15922618.
Jump up^ Dang, Z. C. (2009). “Dose-dependent effects of soy phyto-oestrogen genistein on adipocytes: Mechanisms of action”. Obesity Reviews 10 (3): 342–9. doi:10.1111/j.1467-789X.2008.00554.x. PMID 19207876.
Jump up^ Han, Rui-Min; Tian, Yu-Xi; Liu, Yin; Chen, Chang-Hui; Ai, Xi-Cheng; Zhang, Jian-Ping; Skibsted, Leif H. (2009). “Comparison of Flavonoids and Isoflavonoids as Antioxidants”.Journal of Agricultural and Food Chemistry 57 (9): 3780–5. doi:10.1021/jf803850p.PMID 19296660.
Jump up^ Borrás, Consuelo; Gambini, Juan; López-Grueso, Raúl; Pallardó, Federico V.; Viña, Jose (2010). “Direct antioxidant and protective effect of estradiol on isolated mitochondria”.Biochimica et Biophysica Acta 1802 (1): 205–11. doi:10.1016/j.bbadis.2009.09.007.PMID 19751829.
^ Jump up to:^a ^b Bandele, Omari J.; Osheroff, Neil (2007). “Bioflavonoids as Poisons of Human Topoisomerase IIα and IIβ”. Biochemistry 46 (20): 6097–108. doi:10.1021/bi7000664.PMC 2893030. PMID 17458941.
^ Jump up to:^a ^b Markovits, Judith; Linassier, Claude; Fossé, Philippe; Couprie, Jeanine; Pierre, Josiane; Jacquemin-Sablon, Alain; Saucier, Jean-Marie; Le Pecq, Jean-Bernard; Larsen, Annette K. (September 1989). “Inhibitory effects of the tyrosine kinase inhibitor genistein on mammalian DNA topoisomerase II”. Cancer Research 49 (18): 5111–7.PMID 2548712.
^ Jump up to:^a ^b López-Lázaro, Miguel; Willmore, Elaine; Austin, Caroline A. (2007). “Cells Lacking DNA Topoisomerase IIβ are Resistant to Genistein”. Journal of Natural Products 70 (5): 763–7. doi:10.1021/np060609z. PMID 17411092.
Jump up^ Mann, Giovanni E; Bonacasa, Barbara; Ishii, Tetsuro; Siow, Richard CM (2009). “Targeting the redox sensitive Nrf2–Keap1 defense pathway in cardiovascular disease: Protection afforded by dietary isoflavones”. Current Opinion in Pharmacology 9 (2): 139–45. doi:10.1016/j.coph.2008.12.012. PMID 19157984.
^ Jump up to:^a ^b Tandon, V.; Pal, P.; Roy, B.; Rao, H. S. P.; Reddy, K. S. (1997). “In vitro anthelmintic activity of root-tuber extract of Flemingia vestita, an indigenous plant in Shillong, India”. Parasitology Research 83 (5): 492–8. doi:10.1007/s004360050286.PMID 9197399.
Jump up^ Kar, Pradip K; Tandon, Veena; Saha, Nirmalendu (2002). “Anthelmintic efficacy ofFlemingia vestita: Genistein-induced effect on the activity of nitric oxide synthase and nitric oxide in the trematode parasite, Fasciolopsis buski“. Parasitology International 51 (3): 249–57. doi:10.1016/S1383-5769(02)00032-6. PMID 12243779.
Jump up^ Toner, E.; Brennan, G. P.; Wells, K.; McGeown, J. G.; Fairweather, I. (2008). “Physiological and morphological effects of genistein against the liver fluke, Fasciola hepatica“. Parasitology 135 (10): 1189–203. doi:10.1017/S0031182008004630.PMID 18771609.
Jump up^ Tandon, Veena; Das, Bidyadhar; Saha, Nirmalendu (2003). “Anthelmintic efficacy ofFlemingia vestita (Fabaceae): Effect of genistein on glycogen metabolism in the cestode,Raillietina echinobothrida“. Parasitology International 52 (2): 179–86. doi:10.1016/S1383-5769(03)00006-0. PMID 12798931.
Jump up^ Das, B.; Tandon, V.; Saha, N. (2004). “Anthelmintic efficacy of Flemingia vestita(Fabaceae): Alteration in the activities of some glycolytic enzymes in the cestode,Raillietina echinobothrida“. Parasitology Research 93 (4): 253–61. doi:10.1007/s00436-004-1122-8. PMID 15138892.
Jump up^ Das, Bidyadhar; Tandon, Veena; Saha, Nirmalendu (2006). “Effect of isoflavone from Flemingia vestita (Fabaceae) on the Ca2+ homeostasis in Raillietina echinobothrida, the cestode of domestic fowl”. Parasitology International 55 (1): 17–21.doi:10.1016/j.parint.2005.08.002. PMID 16198617.
Jump up^ Das, Bidyadhar; Tandon, Veena; Lyndem, Larisha M.; Gray, Alexander I.; Ferro, Valerie A. (2009). “Phytochemicals from Flemingia vestita (Fabaceae) and Stephania glabra(Menispermeaceae) alter cGMP concentration in the cestode Raillietina echinobothrida“.Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology 149 (3): 397–403. doi:10.1016/j.cbpc.2008.09.012. PMID 18854226.
Jump up^ Naguleswaran, Arunasalam; Spicher, Martin; Vonlaufen, Nathalie; Ortega-Mora, Luis M.; Torgerson, Paul; Gottstein, Bruno; Hemphill, Andrew (2006). “In Vitro Metacestodicidal Activities of Genistein and Other Isoflavones against Echinococcus multilocularis andEchinococcus granulosus“. Antimicrobial Agents and Chemotherapy 50 (11): 3770–8.doi:10.1128/AAC.00578-06. PMC 1635224. PMID 16954323.
Jump up^ Si, Hongwei; Liu, Dongmin; Si, Hongwei; Liu, Dongmin (2007). “Phytochemical Genistein in the Regulation of Vascular Function: New Insights”. Current Medicinal Chemistry 14(24): 2581–9. doi:10.2174/092986707782023325. PMID 17979711.
^ Jump up to:^a ^b Morito, Keiko; Hirose, Toshiharu; Kinjo, Junei; Hirakawa, Tomoki; Okawa, Masafumi; Nohara, Toshihiro; Ogawa, Sumito; Inoue, Satoshi; Muramatsu, Masami; Masamune, Yukito (2001). “Interaction of Phytoestrogens with Estrogen Receptors α and β”. Biological & Pharmaceutical Bulletin 24 (4): 351–6. doi:10.1248/bpb.24.351. PMID 11305594.
Jump up^ Hwang, Ye Won; Kim, Soo Young; Jee, Sun Ha; Kim, Youn Nam; Nam, Chung Mo (2009). “Soy Food Consumption and Risk of Prostate Cancer: A Meta-Analysis of Observational Studies”. Nutrition and Cancer 61 (5): 598–606.doi:10.1080/01635580902825639. PMID 19838933.
Jump up^ Kim, Su-Hyeon; Kim, Su-Hyeong; Kim, Yong-Beom; Jeon, Yong-Tark; Lee, Sang-Chul; Song, Yong-Sang (2009). “Genistein Inhibits Cell Growth by Modulating Various Mitogen-Activated Protein Kinases and AKT in Cervical Cancer Cells”. Annals of the New York Academy of Sciences 1171: 495–500. Bibcode:2009NYASA1171..495K.doi:10.1111/j.1749-6632.2009.04899.x. PMID 19723095.
Jump up^ Das, Arabinda; Banik, Naren L.; Ray, Swapan K. (2009). “Flavonoids activated caspases for apoptosis in human glioblastoma T98G and U87MG cells but not in human normal astrocytes”. Cancer 116 (1): 164–76. doi:10.1002/cncr.24699. PMC 3159962.PMID 19894226.
Jump up^ Sakamoto, Takako; Horiguchi, Hyogo; Oguma, Etsuko; Kayama, Fujio (2010). “Effects of diverse dietary phytoestrogens on cell growth, cell cycle and apoptosis in estrogen-receptor-positive breast cancer cells”. The Journal of Nutritional Biochemistry 21 (9): 856–64. doi:10.1016/j.jnutbio.2009.06.010. PMID 19800779.
Jump up^ de Lemos, Mário L (2001). “Effects of Soy Phytoestrogens Genistein and Daidzein on Breast Cancer Growth”. The Annals of Pharmacotherapy 35 (9): 1118–21.doi:10.1345/aph.10257. PMID 11573864.
^ Jump up to:^a ^b de Assis, Sonia; Hilakivi-Clarke, Leena (2006). “Timing of Dietary Estrogenic Exposures and Breast Cancer Risk”. Annals of the New York Academy of Sciences 1089: 14–35. Bibcode:2006NYASA1089…14D. doi:10.1196/annals.1386.039.PMID 17261753.
Jump up^ López-Lázaro, Miguel; Willmore, Elaine; Austin, Caroline A. (2007). “Cells Lacking DNA Topoisomerase IIβ are Resistant to Genistein”. Journal of Natural Products 70 (5): 763–7.doi:10.1021/np060609z. PMID 17411092.
Jump up^ Safa, Malek; Foon, Kenneth A.; Oldham, Robert K. (2009). “Drug Immunoconjugates”. In Oldham, Robert K.; Dillman, Robert O. Principles of Cancer Biotherapy (5th ed.). pp. 451–62. doi:10.1007/978-90-481-2289-9_12. ISBN 978-90-481-2277-6.
Jump up^ Raynal, Noël J. M.; Charbonneau, Michel; Momparler, Louise F.; Momparler, Richard L. (2008). “Synergistic Effect of 5-Aza-2′-Deoxycytidine and Genistein in Combination Against Leukemia”. Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 17(5): 223–30. doi:10.3727/096504008786111356. PMID 18980019.
Jump up^ Kuiper, George G. J. M.; Lemmen, Josephine G.; Carlsson, Bo; Corton, J. Christopher; Safe, Stephen H.; van der Saag, Paul T.; van der Burg, Bart; Gustafsson, Jan-Åke (1998). “Interaction of Estrogenic Chemicals and Phytoestrogens with Estrogen Receptor β”.Endocrinology 139 (10): 4252–63. doi:10.1210/endo.139.10.6216. PMID 9751507.
Jump up^ Ju, Young H.; Allred, Kimberly F.; Allred, Clinton D.; Helferich, William G. (2006). “Genistein stimulates growth of human breast cancer cells in a novel, postmenopausal animal model, with low plasma estradiol concentrations”. Carcinogenesis 27 (6): 1292–9.doi:10.1093/carcin/bgi370. PMID 16537557.
Jump up^ Chen, Wen-Fang; Wong, Man-Sau (2004). “Genistein Enhances Insulin-Like Growth Factor Signaling Pathway in Human Breast Cancer (MCF-7) Cells”. The Journal of Clinical Endocrinology & Metabolism 89 (5): 2351–9. doi:10.1210/jc.2003-032065.PMID 15126563.
Jump up^ Yang, Xiaohe; Yang, Shihe; McKimmey, Christine; Liu, Bolin; Edgerton, Susan M.; Bales, Wesley; Archer, Linda T.; Thor, Ann D. (2010). “Genistein induces enhanced growth promotion in ER-positive/erbB-2-overexpressing breast cancers by ER-erbB-2 cross talk and p27/kip1 downregulation”. Carcinogenesis 31 (4): 695–702. doi:10.1093/carcin/bgq007.PMID 20067990.
Jump up^ Helferich, W. G.; Andrade, J. E.; Hoagland, M. S. (2008). “Phytoestrogens and breast cancer: A complex story”. Inflammopharmacology 16 (5): 219–26. doi:10.1007/s10787-008-8020-0. PMID 18815740.
Jump up^ Tonetti, Debra A.; Zhang, Yiyun; Zhao, Huiping; Lim, Sok-Bee; Constantinou, Andreas I. (2007). “The Effect of the Phytoestrogens Genistein, Daidzein, and Equol on the Growth of Tamoxifen-Resistant T47D/PKCα”. Nutrition and Cancer 58 (2): 222–9.doi:10.1080/01635580701328545. PMID 17640169.
Jump up^ Jiang, Xinguo; Patterson, Nicole M.; Ling, Yan; Xie, Jianwei; Helferich, William G.; Shapiro, David J. (2008). “Low Concentrations of the Soy Phytoestrogen Genistein Induce Proteinase Inhibitor 9 and Block Killing of Breast Cancer Cells by Immune Cells”.Endocrinology 149 (11): 5366–73. doi:10.1210/en.2008-0857. PMC 2584580.PMID 18669594.
Jump up^ Kumi-Diaka, James; Rodriguez, Rosanna; Goudaze, Gould (1998). “Influence of genistein (4′,5,7-trihydroxyisoflavone) on the growth and proliferation of testicular cell lines”. Biology of the Cell 90 (4): 349–54. doi:10.1016/S0248-4900(98)80015-4.PMID 9800352.
Jump up^ Mitchell, Julie H.; Cawood, Elizabeth; Kinniburgh, David; Provan, Anne; Collins, Andrew R.; Irvine, D. Stewart (2001). “Effect of a phytoestrogen food supplement on reproductive health in normal males”. Clinical Science 100 (6): 613–8. doi:10.1042/CS20000212.PMID 11352776.
Jump up^ Lutz, Werner K.; Tiedge, Oliver; Lutz, Roman W.; Stopper, Helga (2005). “Different Types of Combination Effects for the Induction of Micronuclei in Mouse Lymphoma Cells by Binary Mixtures of the Genotoxic Agents MMS, MNU, and Genistein”. Toxicological Sciences 86 (2): 318–23. doi:10.1093/toxsci/kfi200. PMID 15901918.
^ Jump up to:^a ^b Jin, Ying; Wu, Heng; Cohen, Eric M.; Wei, Jianning; Jin, Hong; Prentice, Howard; Wu, Jang-Yen (2007). “Genistein and daidzein induce neurotoxicity at high concentrations in primary rat neuronal cultures”. Journal of Biomedical Science 14 (2): 275–84.doi:10.1007/s11373-006-9142-2. PMID 17245525.
Jump up^ Schmidt, Friederike; Knobbe, Christiane; Frank, Brigitte; Wolburg, Hartwig; Weller, Michael (2008). “The topoisomerase II inhibitor, genistein, induces G2/M arrest and apoptosis in human malignant glioma cell lines”. Oncology Reports 19 (4): 1061–6.doi:10.3892/or.19.4.1061. PMID 18357397.
Jump up^ van Waalwijk van Doorn-Khosrovani, Sahar Barjesteh; Janssen, Jannie; Maas, Lou M.; Godschalk, Roger W. L.; Nijhuis, Jan G.; van Schooten, Frederik J. (2007). “Dietary flavonoids induce MLL translocations in primary human CD34+ cells”. Carcinogenesis 28(8): 1703–9. doi:10.1093/carcin/bgm102. PMID 17468513.
Jump up^ Spector, Logan G.; Xie, Yang; Robison, Leslie L.; Heerema, Nyla A.; Hilden, Joanne M.; Lange, Beverly; Felix, Carolyn A.; Davies, Stella M.; Slavin, Joanne; Potter, John D.; Blair, Cindy K.; Reaman, Gregory H.; Ross, Julie A. (2005). “Maternal Diet and Infant Leukemia: The DNA Topoisomerase II Inhibitor Hypothesis: A Report from the Children’s Oncology Group”. Cancer Epidemiology Biomarkers & Prevention 14 (3): 651–5. doi:10.1158/1055-9965.EPI-04-0602. PMID 15767345.
Jump up^ Azarova, Anna M.; Lin, Ren-Kuo; Tsai, Yuan-Chin; Liu, Leroy F.; Lin, Chao-Po; Lyu, Yi Lisa (2010). “Genistein induces topoisomerase IIbeta- and proteasome-mediated DNA sequence rearrangements: Implications in infant leukemia”. Biochemical and Biophysical Research Communications 399 (1): 66–71. doi:10.1016/j.bbrc.2010.07.043.PMC 3376163. PMID 20638367.
Jump up^ Piotrowska, Ewa; Jakóbkiewicz-Banecka, Joanna; Barańska, Sylwia; Tylki-Szymańska, Anna; Czartoryska, Barbara; Węgrzyn, Alicja; Węgrzyn, Grzegorz (2006). “Genistein-mediated inhibition of glycosaminoglycan synthesis as a basis for gene expression-targeted isoflavone therapy for mucopolysaccharidoses”. European Journal of Human Genetics 14(7): 846–52. doi:10.1038/sj.ejhg.5201623. PMID 16670689.
Jump up^ Ballabio, A. (2009). “Disease pathogenesis explained by basic science: Lysosomal storage diseases as autophagocytic disorders”. International Journal of Clinical Pharmacology and Therapeutics 47 (Suppl 1): S34–8. doi:10.5414/cpp47034.PMID 20040309.
Jump up^ Settembre, Carmine; Fraldi, Alessandro; Jahreiss, Luca; Spampanato, Carmine; Venturi, Consuelo; Medina, Diego; de Pablo, Raquel; Tacchetti, Carlo; Rubinsztein, David C.; Ballabio, Andrea (2007). “A block of autophagy in lysosomal storage disorders”. Human Molecular Genetics 17 (1): 119–29. doi:10.1093/hmg/ddm289. PMID 17913701.
Jump up^ Xu, Li; Farmer, Rebecca; Huang, Xiaoke; Pavese, Janet; Voll, Eric; Irene, Ogden; Biddle, Margaret; Nibbs, Antoinette; Valsecchi, Matias; Scheidt, Karl; Bergan, Raymond (2010). “Abstract B58: Discovery of a novel drug KBU2046 that inhibits conversion of human prostate cancer to a metastatic phenotype”. Cancer Prevention Research 3 (12 Supplement): B58. doi:10.1158/1940-6207.PREV-10-B58.
Jump up^ “New Drug Stops Spread of Prostate Cancer” (Press release). Northwestern University. April 3, 2012. Retrieved September 27, 2014.
Jump up^ Chen, Chun-Lin; Levine, Alexandra; Rao, Asha; O’Neill, Karen; Messinger, Yoav; Myers, Dorothea E.; Goldman, Frederick; Hurvitz, Carole; Casper, James T.; Uckun, Fatih M. (1999). “Clinical Pharmacokinetics of the CD19 Receptor-Directed Tyrosine Kinase Inhibitor B43-Genistein in Patients with B-Lineage Lymphoid Malignancies”. The Journal of Clinical Pharmacology 39 (12): 1248–55. doi:10.1177/00912709922012051. PMID 10586390.

External links

Development and scale-up of the synthetic process for genistein preparation are described. The process was designed with consideration for environmental and economical aspects and optimized in a laboratory scale. In a scale up, on every step quantity of the environmentally unfriendly substrates or solvents was reduced without compromising the quality of the final product, and the waste load was significantly diminished. The optimal duration times of the individual stages were determined, and the number of operations was reduced, leading to lowering of energy consumption. Elaborated process secures good yield and quality expected for pharmaceutical substances.

Technical Process for Preparation of Genistein

Katarzyna Filip^*, Ewa Kleczkowska-Plichta, Zbigniew Araźny, Grzegorz Grynkiewicz, Magdalena Polowczyk,Krzysztof Gabarski, and Kinga Trzcińska

Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.5b00425

Publication Date (Web): June 03, 2016

*E-mail: k.filip@ifarm.eu.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00425

Genistein
Names


IUPAC name 5,7-Dihydroxy-3-(4-hydroxyphenyl)chromen-4-one
Other names 4′,5,7-Trihydroxyisoflavone
Identifiers
CAS Number	446-72-0
ChEBI	CHEBI:28088
ChEMBL	ChEMBL44
ChemSpider	4444448
DrugBank	DB01645
IUPHAR/BPS	2826
Jmol 3D model	Interactive image
KEGG	C06563
PubChem	5280961
UNII	DH2M523P0H
InChI [show]
SMILES [show]
Properties
Chemical formula	C₁₅H₁₀O₅
Molar mass	270.24 g·mol⁻¹
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Akiyama, T., et al.: J. Biol. Chem., 262, 5592 (1987), O’Dell, T.J., et al.: Nature, 353, 588 (1991), Aharonovits, O., et al.: Biochim Biophys. Acta, 1112, 181 (1992), Platanias, L.C., et al.: J. Biol. Chem., 267, 24053 (1992), Yoshida, H., et al.: Biochim. Biophys. Acta, 1137, 321 (1992), Uckun, F.M., et al.: Science, 267, 886 (1995), Merck Index 12th ed. 4395, Huang, R.Q.; Fang, M.J.; Dillon, G.H., Mol. Brain Res. 67: 177-183 (1999)

//////BIO-300, G-2535, PTI-G-4660, SIPI-9764-I, PTIG-4660, SIPI-9764I, Genistein, phase 2, national cancer institute

Oc1ccc(cc1)C\3=C\Oc2cc(O)cc(O)c2C/3=O

Supporting Info

Start of the Euro 2016

DR ANTHONY’S ORGANIC SPECTROSCOPY INTERNATIONAL HITS 4 LAKH VIEWS

June 11, 2016 1:37 pm / 1 Comment on DR ANTHONY’S ORGANIC SPECTROSCOPY INTERNATIONAL HITS 4 LAKH VIEWS

ORGANIC SPECTROSCOPY INTERNATIONAL HITS 4 LAKH VIEWS

LINK https://orgspectroscopyint.blogspot.in/

SEE SNAPSHOT

ORGANIC SPECTROSCOPY INTERNATIONAL

Organic Chemists from Industry and academics to Interact on Spectroscopy Techniques for Organic Compounds ie NMR, MASS, IR, UV Etc. Starters, Learners, advanced, all alike, contains content which is basic or advanced, by Dr Anthony Melvin Crasto, Worlddrugtracker.

An Indian helping millions

MAKING INDIANS FEEL PROUD

//////

Perspectives on Anti-Glycan Antibodies Gleaned from Development of a Community Resource Database

June 11, 2016 10:24 am / Leave a comment

Antibodies are used extensively for a wide range of basic research and clinical applications. While an abundant and diverse collection of antibodies to protein antigens have been developed, good monoclonal antibodies to carbohydrates are much less common. Moreover, it can be difficult to determine if a particular antibody has the appropriate specificity, which antibody is best suited for a given application, and where to obtain that antibody. Herein, we provide an overview of the current state of the field, discuss challenges for selecting and using antiglycan antibodies, and summarize deficiencies in the existing repertoire of antiglycan antibodies. This perspective was enabled by collecting information from publications, databases, and commercial entities and assembling it into a single database, referred to as the Database of Anti-Glycan Reagents (DAGR). DAGR is a publicly available, comprehensive resource for anticarbohydrate antibodies, their applications, availability, and quality

Monoclonal antibodies have transformed biomedical research and clinical care. In basic research, these proteins are used widely for a myriad of applications, such as monitoring/detecting expression of biomolecules in tissue samples, activating or antagonizing various biological pathways, and purifying antigens. To illustrate the magnitude and importance of the antibody reagent market, one commercial supplier sells over 50 000 unique monoclonal antibody clones. In a clinical setting, antibodies are used frequently as therapeutic agents and for diagnostic applications. As a result, monoclonal antibodies are a multibillion dollar industry, with antibody therapeutics estimated at greater than $40 billion annually, diagnostics at roughly $8 billion annually, and antibody reagents at $2 billion annually as of 2012

Perspectives on Anti-Glycan Antibodies Gleaned from Development of a Community Resource Database

Eric Sterner, Natalie Flanagan, and Jeffrey C. Gildersleeve^*

Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States

ACS Chem. Biol., Article ASAP

DOI: 10.1021/acschembio.6b00244

Publication Date (Web): May 25, 2016

*E-mail: gildersj@mail.nih.gov.

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

http://pubs.acs.org/doi/full/10.1021/acschembio.6b00244

Jeffrey C. Gildersleeve, Ph.D.

Senior Investigator

Chemical Biology Laboratory

Head, Chemical Glycobiology Section

Link to additional information about Dr. Gildersleeve’s research.

Areas of Expertise

1) glycan array technology, 2) cancer biomarkers, 3) cancer vaccines, 4) synthesis of carbohydrate antigens

Contact Info

Jeffrey C. Gildersleeve, Ph.D.
Center for Cancer Research
National Cancer Institute
Building 376, Room 208
Frederick, MD 21702-1201
Ph: 301-846-5699
gildersj@mail.nih.gov (link sends e-mail)

Permalink

The Gildersleeve group works at the interface of chemistry, glycobiology, and immunology. We use chemical approaches to 1) aid the design and development of cancer and HIV vaccines, 2) identify clinically useful biomarkers, and 3) better understand the roles of carbohydrates in cancer and HIV immunology. To facilitate these studies, we have developed a glycan microarray that allows high-throughput profiling of serum anti-glycan antibody populations. A number of other groups have also developed glycan arrays; our array is unique in that we use multivalent neoglycoproteins as our array components. This format allows us to readily translate array results to other applications and affords novel approaches to vary glycan presentation.

The main focus of our current and future research is to study the roles of anti-glycan antibodies in the development, progression, and treatment of cancer. These projects are shedding new light on how cancer vaccines work and are uncovering new biomarkers for the early detection, diagnosis, and prognosis of cancer. In particular, we are studying immune responses induced by PROSTVAC-VF, a cancer vaccine in Phase III clinical trials for the treatment of advanced prostate cancer. In addition, we are identifying biomarkers for the early detection and prognosis of ovarian and lung cancer. These projects are highly collaborative in nature and are focused on translating basic research from the bench to the clinic. We rely heavily on glycan array technology to study immune responses to carbohydrates, and we continually strive to improve this technology. First, carbohydrate-protein interactions often involve formation of multivalent complexes. Therefore, presentation is a key feature of recognition. We have developed several new approaches to vary carbohydrate presentation on the surface of the array, including methods to vary glycan density and neoglycoprotein density. Second, we use synthetic organic chemistry to obtain a diverse set of tumor-associated carbohydrates and glycopeptides to populate our array.

Collaborations and Carbohydrate Microarray Screening. We are frequently asked to screen lectins, antibodies, and other entities on our array. Although we are not a core facility and do not provide screening services per se, we are happy to collaborate on many projects. Please contact Jeff Gildersleeve for more details.

Scientific Focus Areas:

Chemical Biology, Immunology

CBL's Eric Sterner wins NIH FARE Award

a small clip

CBL’s Eric Sterner wins NIH FARE Award

Dr. Eric Sterner, a postdoctoral CRTA Fellow in the Gilderlseeve Lab was presented with a FARE award for his abstract entitled, “Profiling Mutational Significance in Germline-to-Affinity Mature 3F8 Variants” in the NIH-wide FARE 2016 competition. This award is given to abstracts that are deemed outstanding based on scientific merit, originality, experimental design and overall quality and presentation. FARE 2016 is sponsored by the NIH Scientific Directors, the Office of Intramural Training & Education and FelCom. The FARE 2016 Award is a $1000 travel grant to attend and present this work at a scientific meeting within the United States.

Natalie Flanagan

Postbaccalaureate Fellow – Cancer Research Training Award (CRTA) at National Cancer Institute (NCI)

https://www.linkedin.com/in/natalie-flanagan-602a98109

Experience

Postbaccalaureate Fellow – Cancer Research Training Award (CRTA)

National Cancer Institute (NCI)

June 2015 – Present (1 year 1 month)Frederick, Maryland

Organic Chemistry Lab TA

University of Maryland

September 2014 – May 2015 (9 months)College Park, Maryland

– Ran on section of the Organic Chemistry I laboratory course for two semesters
– Worked with students in a laboratory setting and office hours to help them understand course materials and experimental procedures
– Worked with professors and other TAs to help develop and grade examinations

Summer Intern

Pfizer

June 2013 – August 2013 (3 months)Groton, Connecticut

– Used protein crystallization to research ligand binding in a protein kinase system
– Learned a variety of laboratory techniques, including: expression and purification of proteins, and various protein crystallization techniques
– Gained a basic knowledge for how to interpret electron density maps used in three-dimensional protein structure determination
– Presented my research project at an internal poster presentation

Education

University of Maryland College Park

Bachelor’s Degree, Cell Biology and Genetics

2011 – 2015

Activities and Societies: Organic Chemistry Tutor – Primannum Honor Society, Chemistry TA, Phi Beta Kappa, Clinical Volunteer – HSC Pediatric Center

Ledyard High School

High School, General Studies

2007 – 2011

//////////Anti-Glycan Antibodies, Gleaned, Community Resource Database

FDA approves vaccine Vaxchora to prevent cholera for travelers

June 11, 2016 1:36 am / Leave a comment

FDA approves vaccine to prevent cholera for travelers

06/10/2016 04:22 PM EDT

The U.S. Food and Drug Administration today approved Vaxchora, a vaccine for the prevention of cholera caused by serogroup O1 in adults 18 through 64 years of age traveling to cholera-affected areas. Vaxchora is the only FDA-approved vaccine for the prevention of cholera.

June 10, 2016

Release

Cholera, a disease caused by Vibrio cholerae bacteria, is acquired by ingesting contaminated water or food and causes a watery diarrhea that can range from mild to extremely severe. Often the infection is mild; however, severe cholera is characterized by profuse diarrhea and vomiting, leading to dehydration. It is potentially life threatening if treatment with antibiotics and fluid replacement is not initiated promptly. According to the World Health Organization, serogroup O1 is the predominant cause of cholera globally.

“The approval of Vaxchora represents a significant addition to the cholera-prevention measures currently recommended by the Centers for Disease Control and Prevention for travelers to cholera-affected regions,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research.

While cholera is rare in the U.S., travelers to parts of the world with inadequate water and sewage treatment and poor sanitation are at risk for infection. Travelers to cholera-affected areas have relied on preventive strategies recommended by the CDC to protect themselves against cholera, including safe food and water practices and frequent hand washing.

Vaxchora is a live, weakened vaccine that is taken as a single, oral liquid dose of approximately three fluid ounces at least 10 days before travel to a cholera-affected area.

Vaxchora’s efficacy was demonstrated in a randomized, placebo-controlled human challenge study of 197 U.S. volunteers from 18 through 45 years of age. Of the 197 volunteers, 68 Vaxchora recipients and 66 placebo recipients were challenged by oral ingestion of Vibrio cholerae, the bacterium that causes cholera. Vaxchora efficacy was 90 percent among those challenged 10 days after vaccination and 80 percent among those challenged three months after vaccination. The study included provisions for administration of antibiotics and fluid replacement in symptomatic participants. To prevent transmission of cholera into the community, the study included provisions for administration of antibiotics to participants not developing symptoms.

Two placebo-controlled studies to assess the immune system’s response to the vaccine were also conducted in the U.S. and Australia in adults 18 through 64 years of age. In the 18 through 45 year age group, 93 percent of Vaxchora recipients produced antibodies indicative of protection against cholera. In the 46 through 64 years age group, 90 percent produced antibodies indicative of protection against cholera. The effectiveness of Vaxchora has not been established in persons living in cholera-affected areas.

The safety of Vaxchora was evaluated in adults 18 through 64 years of age in four randomized, placebo-controlled, multicenter clinical trials; 3,235 study participants received Vaxchora and 562 received a placebo. The most common adverse reactions reported by Vaxchora recipients were tiredness, headache, abdominal pain, nausea/vomiting, lack of appetite and diarrhea.

The FDA granted the Vaxchora application fast track designation and priority review status. These are distinct programs intended to facilitate and expedite the development and review of medical products that address a serious or life-threatening condition. In addition, the FDA awarded the manufacturer of Vaxchora a tropical disease priority review voucher, under a provision included in the Food and Drug Administration Amendments Act of 2007. This provision aims to encourage the development of new drugs and biological products for the prevention and treatment of certain tropical diseases.

Vaxchora is manufactured by PaxVax Bermuda Ltd., located in Hamilton, Bermuda.

Company	PaxVax Inc.
Description	Live attenuated vaccine against Vibrio cholerae
Molecular Target
Mechanism of Action	Vaccine
Therapeutic Modality	Preventive vaccine: Viral vaccine

Latest Stage of Development	Registration
Standard Indication	Cholera
Indication Details	Prevent cholera infection; Treat cholera
Regulatory Designation	U.S. – Fast Track (Prevent cholera infection); U.S. – Priority Review (Prevent cholera infection)

FDA Approves Vaxchora, PaxVax’s Single-Dose Oral Cholera Vaccine

Vaxchora™ is the only approved vaccine in the U.S. for protection against cholera

June 10, 2016 04:32 PM Eastern Daylight Time

REDWOOD CITY, Calif.—-PaxVax, today announced that it has received marketing approval from the United States (U.S.) Food and Drug Administration (FDA) for Vaxchora, a single-dose oral, live attenuated cholera vaccine indicated for use in adults 18 to 64 years of age. Vaxchora is the only vaccine available in the U.S. for protection against cholera and the only single-dose vaccine for cholera currently licensed anywhere in the world.

FDA Approves Vaxchora, PaxVax’s Single-Dose Oral Cholera Vaccine

“FDA approval of a new vaccine for a disease for which there has been no vaccine available is an extremely rare event. The approval of Vaxchora is an important milestone for PaxVax and we are proud to provide the only vaccine against cholera available in the U.S.,” said Nima Farzan, Chief Executive Officer and President of PaxVax. “We worked closely with the FDA on the development of Vaxchora and credit the agency’s priority review program for accelerating the availability of this novel vaccine. In line with our social mission, we have also begun development programs focused on bringing this vaccine to additional populations such as children and people living in countries affected by cholera.”

“As more U.S. residents travel globally, there is greater risk of exposure to diseases like cholera,” added Lisa Danzig, M.D., Vice President, Clinical Development and Medical Affairs. “Cholera is an underestimated disease that is found in many popular global travel destinations and is thought to be underreported in travelers. Preventative measures such as food and water precautions can be challenging to follow effectively and until now, U.S. travelers have not had access to a vaccine to help protect against this potentially deadly pathogen.”

Cholera is an acute intestinal diarrheal infection acquired by ingesting contaminated water and food. Annually, millions of people around the world are impacted by this extremely virulent disease¹ which can cause death in less than 24 hours if left untreated². More than 80 percent of reported U.S. cases³ are associated with travel to one of the 69 cholera-endemic countries⁴ in Africa, Asia and the Caribbean. A recent report from the Centers for Disease Prevention and Control suggests that the true number of cholera cases in the U.S. is at least 30 times higher than observed by national surveillance systems⁵. The currently recommended intervention to prevent cholera infection is the avoidance of contaminated water and food, but studies have shown that 98 percent of travelers do not comply with these precautions when travelling⁶.

“This important FDA decision is the culmination of years of dedicated work by many researchers,” said Myron M. Levine, MD, DTPH, the Simon and Bessie Grollman Distinguished Professor at the University of Maryland School of Medicine (UM SOM). “For travelers to the many parts of the world where cholera transmission is occurring and poses a potential risk, this vaccine helps protect them from this disease. It is a wonderful example of how public-private partnerships can develop medicines from bench to bedside.” Dr. Levine is co-inventor of the vaccine, along with James B. Kaper, PhD, Chairman of the UM SOM Department of Microbiology and Immunology. In addition, the Center for Vaccine Development at UM SOM worked closely with PaxVax during the development of Vaxchora.

The attenuated cholera vaccine strain used in Vaxchora is CVD 103-HgR, which was in-licensed from the Center for Vaccine Development at UM SOM in 2010. Vaxchora is expected to be commercially available in Q3 2016. Vaxchora will be distributed through PaxVax’s U.S. marketing and sales organization, which currently commercializes Vivotif^®, an FDA-approved oral typhoid fever vaccine.

About Vaxchora (Cholera Vaccine, Live, Oral)

Vaxchora is an oral vaccine indicated for active immunization against disease caused by Vibrio cholerae serogroup O1. Vaxchora is approved for use in adults 18 through 64 years of age traveling to cholera-affected areas. The effectiveness of Vaxchora has not been established in persons living in cholera-affected areas or in persons who have pre-existing immunity due to previous exposure to V. cholerae or receipt of a cholera vaccine. Vaxchora has not been shown to protect against disease caused by V. cholerae serogroup O139 or other non-O1 serogroups.

The FDA approval of Vaxchora is based on positive results from a 10 and 90-day cholera challenge trial, as well as two safety and immunogenicity trials in healthy adults that demonstrated efficacy of more than 90 percent at 10 days and 79 percent at 3 months post vaccination⁷. The most common adverse reactions were tiredness, headache, abdominal pain, nausea/vomiting, lack of appetite and diarrhea. More than 3,000 participants were enrolled in the Phase 3 clinical trial program that evaluated Vaxchora at sites in Australia and the United States.

For the full Prescribing Information, please visit www.vaxchora.com.

Young man drinking contaminated water. Close-up of vibrio cholerae bacteria.

A bacterial disease causing severe diarrhoea and dehydration, usually spread in water

About PaxVax

PaxVax develops, manufactures and commercializes innovative specialty vaccines against infectious diseases for traditionally overlooked markets such as travel. PaxVax has licensed vaccines for typhoid fever (Vivotif) and cholera (Vaxchora), and vaccines at various stages of research and clinical development for adenovirus, anthrax, hepatitis A, HIV, and zika. As part of its social mission, PaxVax is also working to make its vaccines available to broader populations most affected by these diseases. PaxVax is headquartered in Redwood City, California and maintains research and development and Good Manufacturing Practice (GMP) facilities in San Diego, California and Bern, Switzerland and other operations in Bermuda and Europe. More information is available at www.PaxVax.com.

References:

¹ Centers for Disease Control and Prevention. Cholera: General Information. November 2014. http://www.cdc.gov/cholera/general. Accessed June 2016.

² World Health Organization website. Cholera Fact Sheet. July 2015. http://www.who.int/mediacentre/factsheets/fs107/en/. Accessed June 2016.

³ Loharikar A et al. Cholera in the United States, 2001-2011: a reflection of patterns of global epidemiology and travel. Epidemiol Infect. 2015;143(4):695-703. doi:10.1017/S0950268814001186.

⁴ Ali M et al. Updated global burden of cholera in endemic countries. PLoS Negl Trop Dis. 2015; 9: e0003832 doi: 10.1371/journal.pntd.0003832.

⁵ Scallan E et al. Foodborne Illness Acquired in the United States –Major Pathogens. Emerg Infect Dis. 2011. http://dx.doi.org/10.3201/eid1701.P11101.

⁶ Kozicki M et al. Boil it, cook it, peel it or forget it’: does this rule prevent travellers’ diarrhoea?. Int J. Epidemiol. 1985; 14(1):169-72.

⁷ Chen WH et al. Single-Dose Live Oral Cholera Vaccine CVD 103-HgR Protects Against Human Experimental Infection with Vibrio cholerae O1 El Tor. Clinical Infectious Diseases 2016. 62 (11) 1329-1335. doi: 10.1093/cid/ciw145.

Contacts

PaxVax Inc.
Colin Sanford, 415-870-9188
colin.sanford@W2comm.com

/////FDA. vaccine, Vaxchora, choleram travelers, PaxVax Bermuda Ltd.,Hamilton, Bermuda.

Gilteritinib fumarate ギルテリチニブフマル酸塩

June 10, 2016 12:34 pm / Leave a comment

1254053-84-3

Gilteritinib

ASP-2215

Treatment of Acute Myeloid Leukemia

6-ethyl-3-{3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino}-5-[(oxan-4-yl)amino]pyrazine-2-carboxamide

C29H44N8O3, 552.71

Xospata pmda 2018/9/21 JAPAN 2018

A FLT3/AXL inhibitor potentially for the treatment of acute myeloid leukemia.

CAS No. 1254053-43-4 FREE FORM

1254053-84-3 FUMARATE

Astellas Pharma INNOVATOR
Mechanism Of Action	Axl receptor tyrosine kinase inhibitors, Fms-like tyrosine kinase 3 inhibitors, Proto oncogene protein c-kit inhibitors
Who Atc Codes	L01X-E (Protein kinase inhibitors)
Ephmra Codes	L1H (Protein Kinase Inhibitor Antineoplastics)
Indication	Cancer, Hepatic impairment

Gilteritinib(ASP-2215) is a potent FLT3/AXL inhibitor with IC50 of 0.29 nM/<1 nM respectively; shows potent antileukemic activity against AML with either or both FLT3-ITD and FLT3-D835 mutations.
IC50 value: 0.29 nM(FLT3); <1 nM(Axl kinase)
Target: FLT3/AXL inhibitor
ASP2215 inhibited the growth of MV4-11 cells, which harbor FLT3-ITD, with an IC50 value of 0.92 nM, accompanied with inhibition of pFLT3, pAKT, pSTAT5, pERK, and pS6. ASP2215 decreased tumor burden in bone marrow and prolonged the survival of mice intravenously transplanted with MV4-11 cells. ASP2215 may have potential use in treating AML.

SYNTHESIS

PATENT

WO 2010128659

Patent

WO 2015119122

Compound A is 6-ethyl-3 – ({3-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) -5- a (tetrahydro -2H- pyran-4-ylamino) pyrazine-2-carboxamide, its chemical structure is shown below.
[Formula 1]

Gilteritinib fumarate

Gilteritinib fumarate [USAN]

RN: 1254053-84-3

UNII: 5RZZ0Z1GJT

2-Pyrazinecarboxamide, 6-ethyl-3-((3-methoxy-4-(4-(4-methyl-1-piperazinyl)-1-piperidinyl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)-, (2E)-2-butenedioate (2:1)

ASP-2215 hemifumarate
Molecular Formula, 2C29-H44-N8-O3.C4-H4-O4, Molecular Weight, 1221.5108

Astellas Inititaties Phase 3 Registration Trial of gilteritinib (ASP2215) in Relapsed or Refractory Acute Myeloid Leukemia Patients

TOKYO, Japan I October 28, 2015 I Astellas Pharma Inc. (TSE:4503) today announced dosing of the first patient in a randomized Phase 3 registration trial of gilteritinib (ASP2215)versus salvage chemotherapy in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). The primary endpoint of the trial is overall survival (OS).

Gilteritinibis a receptor tyrosine kinase inhibitor of FLT3 and AXL, which are involved in the growth of cancer cells. Gilteritinibhas demonstrated inhibitory activity against FLT3 internal tandem duplication (ITD) as well as tyrosine kinase domain (TKD), two common types of FLT3 mutations that are seen in up to one third of patients with AML.

The gilteritinib Phase 3 trial follows a Phase 1/2 trial, which evaluated doses from 20 to 450 mg once daily. A parallel multi-dose expansion cohort was initiated based on the efficacy seen in the dose escalation phase. Preliminary data from the Phase 1/2 trial presented at the 2015 American Society of Clinical Oncology annual meeting demonstrated a 57.5 percent overall response rate and a 47.2 percent composite Complete Response (CR) rate (CR + CR with incomplete platelet recovery + CR with incomplete hematologic recovery) in 106 patients with FLT3 mutations who received 80 mg and higher doses. Median duration of response was 18 weeks across all doses and median OS was approximately 27 weeks at 80 mg and above in FLT3 mutation positive patients. Common drug-related adverse events (> 10%) observed in the study were diarrhea (13.4%), fatigue (12.4%) and AST increase (11.3%). At the 450 mg dose, two patients reached dose-limiting toxicity (grade 3 diarrhea and ALT/AST elevation) and the maximum tolerated dose was determined to be 300 mg.

On October 27, 2015, the Japanese Ministry of Health, Labor and Welfare (MHLW) announced the selection of gilteritinib as one of the first products designated for SAKIGAKE.

About the Phase 3 Study

The Phase 3 trial is an open-label, multicenter, randomized study of gilteritinib versus salvage chemotherapy in patients with Acute Myeloid Leukemia (AML). The study will enroll 369 patients with FLT3 activating mutation in bone marrow or whole blood, as determined by central lab, AML who are refractory to or have relapsed after first-line AML therapy. Subjects will be randomized in a 2:1 ratio to receive gilteritinib (120 mg) or salvage chemotherapy consisting of LoDAC (low-dose cytarabine), azacitidine, MEC (mitoxantrone, etoposide, and intermediate-dose cytarabine), or FLAG-IDA (fludarabine, cytarabine, and granulocyte colony-stimulating factor with idarubicin). The primary endpoint of the trial is OS. For more information about this trial go to http://www.clinicaltrials.gov, trial identifier NCT02421939.

Gilteritinib was discovered through a research collaboration with Kotobuki Pharmaceutical Co., Ltd., and Astellas has exclusive global rights to develop, manufacture and potentially commercialize gilteritinib.

About Acute Myeloid Leukemia

Acute myeloid leukemia is a cancer that impacts the blood and bone marrow and most commonly experienced in older adults. According to the//www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf” target=”_blank” rel=”nofollow”>American Cancer Society, in 2015, there will be an estimated 20,830 new cases of AML diagnosed in the United States, and about 10,460 cases will result in death.

About SAKIGAKE

The SAKIGAKE designation system can shorten the review period in the following three approaches: 1.) Prioritized Consultation 2.) Substantial Pre-application Consultation and 3.) Prioritized Review. Also, the system will promote development with the following two approaches: 4.) Review Partner System (to be conducted by the Pharmaceuticals and Medical Devices Agency) and 5.) Substantial Post-Marketing Safety Measures.

About Astellas

Astellas Pharma Inc., based in Tokyo, Japan, is a company dedicated to improving the health of people around the world through the provision of innovative and reliable pharmaceutical products. We focus on Urology, Oncology, Immunology, Nephrology and Neuroscience as prioritized therapeutic areas while advancing new therapeutic areas and discovery research leveraging new technologies/modalities. We are also creating new value by combining internal capabilities and external expertise in the medical/healthcare business. Astellas is on the forefront of healthcare change to turn innovative science into value for patients. For more information, please visit our website at http://www.astellas.com/en.

SOURCE: Astellas Pharma

Start of the Euro 2016

////////1254053-43-4, Gilteritinib, ASP-2215, PHASE 3, ASP 2215, Astellas Pharma, Acute Myeloid Leukemia

CCc1c(nc(c(n1)C(=O)N)Nc2ccc(c(c2)OC)N3CCC(CC3)N4CCN(CC4)C)NC5CCOCC5

CCc1c(nc(c(n1)C(=O)N)Nc2ccc(c(c2)OC)N3CCC(CC3)N4CCN(CC4)C)NC5CCOCC5.CCc1c(nc(c(n1)C(=O)N)Nc2ccc(c(c2)OC)N3CCC(CC3)N4CCN(CC4)C)NC5CCOCC5.C(=C/C(=O)O)\C(=O)O

Pexidartinib, PLX-3397

June 10, 2016 12:32 pm / Leave a comment

Pexidartinib

PLX-3397

5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-amine

N-[5-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-2-pyridinyl]-6-(trifluoromethyl)-3-pyridinemethanamine

5-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-N-[[6-(trifluoromethyl)pyridin-3-yl]methyl]pyridin-2-amine hydrochloride

A Multi-targeted tyrosine kinase inhibitor potentially for the treatment of tenosynovial giant cell tumor (TGCT).

CAS 1029044-16-3

C20H15ClF3N5, 417.81

Pexidartinib; 1029044-16-3; PLX-3397; 5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-amine; 5-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-N-[[6-(trifluoromethyl)pyridin-3-yl]methyl]pyridin-2-amine; 5-[(5-Chloro-1h-Pyrrolo[2,3-B]pyridin-3-Yl)methyl]-N-{[6-(Trifluoromethyl)pyridin-3-Yl]methyl}pyridin-2-Amine;

Originator Plexxikon
Developer Barbara Ann Karmanos Cancer Institute; Columbia University; Merck & Co; National Cancer Institute (USA); Plexxikon; University of California at San Francisco
Class 2 ring heterocyclic compounds; Antineoplastics; Fluorine compounds; Pyridines; Pyrroles; Small molecules
Mechanism of Action Fms-like tyrosine kinase 3 inhibitors; Immunomodulators; Macrophage colony stimulating factor receptor antagonists; Proto oncogene protein c-akt inhibitors; Proto oncogene protein c-kit inhibitors

Orphan Drug Status Yes – Giant cell tumour of tendon sheath; Pigmented villonodular synovitis

Phase III Pigmented villonodular synovitis
Phase II Glioblastoma; Malignant melanoma; Prostate cancer
Phase I/II Breast cancer; Leukaemia; Peripheral nervous system diseases; Sarcoma; Solid tumours
Phase I Gastrointestinal stromal tumours
No development reported Neurological disorders; Rheumatoid arthritis
Discontinued Acute myeloid leukaemia; Hodgkin’s disease

Most Recent Events

25 May 2016 Plexxikon and AstraZeneca plan the MEDIPLEX phase I trial for Solid tumours (Combination therapy, Metastatic disease) in France (NCT02777710)
05 Apr 2016 Daiichi Sankyo plans a phase I trial for Solid tumours (Late-stage disease, Second-line therapy or greater) in Taiwan (PO) (NCT02734433)
11 Mar 2016 Plexxikon re-initiates enrolment in a phase Ib trial in Solid tumours and Gastrointestinal stromal tumours in USA (NCT02401815)

Plexxikon, a subsidiary of Daiichi Sankyo, is developing pexidartinib, a dual Fms/Kit and FIt3-ITD inhibitor, for treating cancer.

Image result for Plexxikon,

Image result for pexidartinib

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Multi-targeted receptor tyrosine kinase inhibitor of CSF1R, c-Kit, and FLT3 (IC50 values 13 nM, 27 nM, and 11 nM, respectively) Administration of PLX3397 reduced CIBP, induced substantial intratumoral fibrosis, and was also highly efficacious in reducing tumor cell growth, formation of new tumor colonies in bone, and pathological tumor-induced bone remodeling. PLX3397 is superior to imatinib in the treatment of malignant peripheral nerve sheath tumor (MPNST), and the combination of PLX3397 with a TORC1 inhibitor could provide a new therapeutic approach for the treatment of this disease.

Plexxikon is conducting phase III clinical studies with PLX-3397 for the treatment of pigmented villonodular synovitis. Phase II clinical studies are ongoing for the oral treatment of melanoma and glioblastoma multiforme. Additional early clinical trials are underway for the treatment of metastatic breast cancer, for the treatment of prostate cancer (adenocarcinoma), and for the treatment of malignant peripheral nerve sheath tumor. No recent development has been reported from preclinical studies for the treatment of systemic lupus erythematosus and for the treatment of multiple sclerosis. Prior to patient enrollment, a phase I clinical trial by Plexxikon for the treatment of rheumatoid arthritis was withdrawn. Daiichi Sankyo (parent of Plexxikon) decided to discontinue phase II trials of the product for the treatment of castration-resistant prostate cancer and for the treatment of Hodgkin’s lymphoma after reviewing its clinical study results and also have discontinued phase II studies for the treatment of acute myeloid leukemia due to strategic reasons.

In 2014, orphan drug designation was assigned to the compound in the US for the treatment of pigmented villonodular synovitis andf giant cell tumor of the tendon sheath. In 2015, the compound was granted orphan designation in the E.U. for the treatment of tenosynovial giant cell tumor, localised and diffuse type. In the same year, the product was granted breakthrough therapy designation for the treatment of tenosynovial giant cell tumor (TGCT) where surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity.

C-fms and c-kit arc both type III transmembrane receptor protein tyrosine kinases (RPTKs) that regulate key signal transduction cascades that control cellular growth and proliferation. Both receptors have similar structural features comprising five extracellular immunoglobulin (IG) domains, a single transmembrane domain, and a split cytoplasmic kinase domain separated by a kinase insert segment.

c-Fms
C-fms is a member of the family of genes originally isolated from the Susan McDonough strain ot teline sarcoma viruses, The cellular proto-oncogene FMS (c-fms, cellular feline McDonough sarcoma) codes for the receptor for the macrophage colony-stimuktmg tactor (M- CSF) C-fms is crucial for the growth and differentiation of the monocyte-macrophage lineage, and upon binding of Vf-CSF to the extracellular domain of c-fms, the receptor dimeπzes and trans- autophosphorylates cytoplasmic tyrosine residues

M-CSF, first described by Robinson and co-workers (Blood 1969, 33 396-9), is a cytokine that controls the production, differentiation, and function of macrophages M-CSF stimulates differentiation of progenitor cells to mature monocytes, and prolongs the survival of monocytes Furthermore, M-CSF enhances cytotoxicity, superoxide production, phagocytosis, chemota\is, and secondary cytokine production of additional factors in monocytes and macrophages Examples of such additional factors include granulocyte colony stimulating lactor (G-CSF) interleukin-6 (IL-6), and mterleukm-8 (IL-8) M-CSF stimulates hematopoiesis, promotes differentiation and proliferation of osteoclast progenitor cells, and has profound effects on lipid metabolism Furthermore, M-CSF is important in pregnancy Physiologically, large amounts of M-CSF are produced in the placenta, and M-CSF is believed to play an essential role in trophoblast differentiation (Motoyoshi, lnt J Hematol 1998, 67 109-22) l hc elevated semm levels of M-CSF m early pregnancy may participate in the immunologic mechanisms responsible for the maintenance of the pregnancy (Flanagan & Lader, Curr Opm Hematol 1998, 5 181-5)

Related to c-fms and c-kit are two p_latelet -derived growth factor receptors, alpha (i e , pdgfra) and beta (pdgfrb) (PDGF) 1 he gene coding for pdgfra is located on chromosome 4ql 1 -q!2 in the same region of chromosome 4 as the oncogene coding for c-kit The genes coding for pdgfra and c-fms appear to have evolved from a common ancestral gene by gene duplication, inasmuch as these two genes are tandemly linked on chromosome 5 They are oriented head to tail with the 5-pnme exon of the c-fms gene located only 500 bp from the last 3-pπme exon of the gene coding for pdgfra Most gastrointestinal stromal tumors (GIST) have activating mutations in c-kit and most patients with GISTs respond well to Gleevec, which inhibits c-kit Hemπch et al (Science 2003, 299 “OS-IO) have shown that approximately 35% of GISTs lacking c-krt mutations, have intragenic activation mutations m tht gene encoding pdgfra, and that tumors expressing c-kit or pdgfrd are indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression Thus, c kit and pdgfra mutations appear to be alternative and mutually exclusive oncogenic mechanisms m GISTs [0007} Similarly, the observation that production of M-CSF, the major macrophage growth factor, is increased in tissues during inflammation points out a role for c-frns in diseases, such as for example inflammatory diseases. More particularly, because elevated levels of M-CSF are found in the disease state, modulation of the activity of c-fms can ameliorate disease associated with increased levels of M-CSF.

c-Kit
The Stem Cell Factor (SCF) receptor c-kit plays an important role in the development of melanocytes and mast, germ and hematopoietic cells. Stem Cell Factor (SCF) is a protein encoded by the Sl locus, and has also been called “kit ligand” (KL) and mast cell growth factor (MGF), based on the biological properties used to identify it (reviewed in Tsujimura, Pathol Int 1996, 46:933-938; Loveland, et al., J. Endocrinol 1997, 153:337-344; Vliagoftis, et al,, Clin Immunol 1997, 100:435-440; Broudy, Blood 1997, 90: 1345-1364; Pignon, Hermatol Cell Ther 1997, 39: 1 14-1 16; and Lyman, et al., Blood 1998, 91 : 1 101 -1 134.). Herein the abbreviation SCF refers to the physiological ligand for c-kit.

SCF is synthesized as a transmembrane protein with a molecular weight of 220 or 248 Dalton, depending on alternative splicing of the mRNA to encode exon 6. The larger protein can be proteolytically cleaved to form, a soluble, glycosylated protein which noncovalently dimerizcs. Both the soluble and membrane-bound forms of SCF can bind to and activate c-kit. For example, in the skin, SCF is predominantly expressed by fibroblasts, keratinocytes, and endothelial cells, which modulate the activity of melanocytes and mast cells expressing c-kit. In bone, marrow stromal cells express SCF and regulate hematopoiesis of c-kit expressing stem cells. In the gastrointestinal tract, intestinal epithelial cells express SCF and affect the interstitial cells of Cajal and intraepithelial lymphocytes. In the testis, Sertoli cells and granulosa cells express SCF which regulates spermatogenesis by interaction with c-kit on germ cells.

PATENT

WO 2008063888

PATENT

WO 2008064265

PATENT

WO 2008064255

PATENT

WO 2012158957

Fragments in the clinic: PLX3397

Practical Fragments covers a wide variety of journals. J. Med. Chem., Bioorg. Med. Chem. Lett., Drug Disc. Today, and ACS Med. Chem. Lett. are all well-represented, but we also range further afield, from biggies such asNature and Science to more niche titles such as ChemMedChem, Acta. Cryst. D., and Anal. Chim. Acta. The increasingly clinical relevance of fragment-based approaches is highlighted by a recent paper by William Tap and a large group of collaborators appearing in the New England Journal of Medicine. This reports on the results of the Daiichi Sankyo (née Plexxikon) drug PLX3397 in a phase I trial for tenosynovial giant-cell tumor, a rare but aggressive cancer of the tendon sheath.

The story actually starts with a 2013 paper by Chao Zhang and his Plexxikon colleagues in Proc. Nat. Acad. Sci. USA. The researchers were interested in inhibiting the enzymes CSF1R (or FMS) and KIT; both kinases are implicated in cancer as well as inflammatory diseases. The team started with 7-azaindole, the same fragment they used to discover vemurafenib. Structural studies of an early derivative, PLX070, revealed a hydrogen bond between the ligand oxygen and a conserved backbone amide. Further building led to PLX647, with good activity against both CSF1R and KIT. Selectivity profiling against a panel of 400 kinases revealed only two others with IC₅₀values < 0.3 µM. The molecule was active in cell-based assays, had good pharmacokinetics in mice and rats, and was active in rodent models of inflammatory disease.

The new paper focuses on the results of a clinical trial with PLX3397, a derivative of PLX647. Despite its close structural similarity to PLX647, it binds to CSF1R in a slightly different manner. Both inhibitors bind to the inactive form of the kinase, but PLX3397 also recruits the so-called juxtamembrane domain of the kinase to stabilize this autoinhibited conformation. Pharmacokinetic and pharmacodynamics studies in animals were also positive.

http://practicalfragments.blogspot.in/2015/10/fragments-in-clinic-plx3397.html

Tenosynovial giant-cell tumor seems to be dependent on CSF1R, so the researchers performed a phase 1 dose-escalation study with an extension in which patients treated with the chosen phase 2 dose were treated longer. Of the 23 patients in this extension, 12 had a partial response and 7 had stable disease. A quick search ofclinicaltrials.gov reveals that PLX3397 is currently in multiple trials for several indications, including a phase 3 trial for giant cell tumor of the tendon sheath.

Several lessons can be drawn from these studies. First, as the authors note, one fragment can give rise to multiple different clinical candidates. Indeed, in addition to vemurafenib, 7-azaindole was also the starting point forAZD5363. This is a good counterargument to those who believe that novelty is essential in fragments.

A second, related point is that selectivity is also not necessary for a fragment. The fact that 7-azaindole comes up so frequently as a kinase-binding fragment has not prevented researchers from growing it into remarkably selective inhibitors. An obvious corollary is that even subtle changes to a molecule can have dramatic effects: the added pyridyl nitrogen in PLX3397 is essential for stabilizing a unique conformation of the enzyme.

NEW PATENT

PEXIDARTINIB BY DAIICHI

WO-2016179412

The compound named, [5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine, which is also known as pexidartinib, is effective for treating subjects suffering from or at risk of a c-Kit and/or c-Fms and/or Flt3 mediated disease or condition. Suitable compounds, including pexidartinib or a salt thereof, for the treatment of such diseases and conditions are disclosed in U.S. Patent 7,893,075, U.S.

Publication No. 2014-0037617 and U.S. Publication No. 2013-0274259, the disclosures of all of which are incorporated herein by reference in their entirety.

There remains a need in developing new versatile and facile processes for the efficient preparation of pexidartinib and other similar molecules, especially in an industrial scale.

Example 1. Synthesis of [5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- (6-trifluoromethyl-pyridin-3-ylmethyl)-amine:

Step 1: Conversion of A to Ilia

The reactor was charged with Compound A (1000 gm, 1.0 eq.), Compound B (497 gm, 1.05 eq.), tetrabutylammonium hydrogen sulfate (31.6 gm, 0.03 eq.) and isopropanol (12 L, 11.8 vol). The reaction mixture was stirred for at least about an hour to obtain a near clear, yellow solution. Then potassium ie/ -pentoxide (73 mL, 0.04 eq.) was added over 30 seconds. The reaction mixture was stirred at about 15-25°C for about 20-24 hours. The reaction was monitored by HPLC. When the content of compound Ilia was more than 80%, the reaction was deemed complete. The reaction mixture was cooled to about 0-10°C and then stirred for at least about 2 hours. The precipitate was filtered, washed with 3 L isopropanol that had been cooled to 0°C and dried to provide compound Ilia as a white solid (1.34 kg, 91.2% yield, 97.7% purity by HPLC). 1H NMR (DMSO-d6): δ (ppm) 11.8 (s, NH), 8.50-8.51 (d, 1H), 8.17 (d, 1H), 7.85-7.88 (dd, 1H), 7.82 (d, 1H), 7.41 (S, 1H), 7.29-7.31 (d, 1H), 6.04 (s, 2H), and 1.35 (s, 18H).

[0073] Alternatively, potassium ie/ -pentoxide can also be used in this reaction as a 25% solution in toluene.

Step 2: Conversion of Ilia to IV

The reactor was charged with compound Ilia (1.1 kg, 1 eq.) and acetonitrile (8.8 L, 12.4 vol) and the reaction mixture was stirred. Then triethylsilane (1.35 kg, 5 eq.) was added at about

15-30°C over at least about 10 minutes. Then trifluoroacetic acid (2.38 kg, 9 eq.) was added to the reactor at about 15-30°C over at least about 30 minutes. The reaction mixture was heated at about 55-65°C over at least about 4 hours. It was then stirred at about 55-65°C for about 20-48 hours. The reaction was monitored by HPLC. When the content of compound Ilia was less than about 1%, the reaction was deemed complete. The reaction mixture was cooled to about 45-55°C and then a) concentrated to 3.3 L under vacuum and b) water (8.25 L) was charged. Steps a) and b) were repeated 4 times. The reaction mixture was then heated at about 45-60°C and stirred for bout 1-3 hours. It was then cooled to about 0-10°C over at least about 2 hours and it was stirred at about 0-10°C for about 2-4 hours. The precipitate was filtered, washed with 2.2 L water and then with heptane (1.1 L) and dried to provide the TFA salt of compound IV as an off-white solid (673.3 gm, 77.9% yield, 99.7% purity by HPLC). 1H NMR (DMSO-d6): δ (ppm) 11.78 (s, COOH), 8.18 (d, 1H), 8.08-8.09 (broad doublet, 2H), 7.93-7.94 (d, 1H), 7.81-7.84 (dd, 1H), 7.47-7.48 (d, 1H), 6.90-6.93 (d, 1H), 3.92 (s, 2H).

Step 3: Conversion of IV to I

[0074] The reactor was charged with compound IV (663.3 gm, 1 eq.), compound V (623.2 gm, 2.0 eq.) and acetonitrile (13.3 L). The reaction mixture was stirred for about 5-10 minutes at room temperature. Triethylsilane (1531.6 gm, 7.4 eq.) was then added to the reactor over at least about 10 minutes at or less than about 30°C. Trifluoroacetic acid (1542.5 gm, 7.6 eq.) was added to the reactor over at least about 10 minutes at or less than about 30°C. The reaction mixture was stirred for at least about 30 minutes at about 15-30°C. It was then heated to about 70-82°C over at least about one hour and then stirred at about 70-82°C for about 20-48 hours. The reaction was monitored by HPLC. When the content of compound IV was less than about 1%, the reaction was deemed complete.

[0075] The reaction mixture was cooled to room temperature, the acetonitrile layer was separated and concentrated. Then water (7.96 L) was charged and the reaction mixture was concentrated to 6.64 L under vacuum providing a tri-phasic mixture. It was then cooled to 15- 25°C, charged with ethyl acetate (10.6 L) and stirred providing a biphasic mixture. It was cooled to 0-10°C, charged with a 25% NaOH solution in water until a pH of about 8-9 was reached with vigorous stirring, heated to about 65-75°C and stirred at about 65-75° for about 30 minutes. The organic layer was separated, and water (3.98 L) was charged and the reaction mixture was heated at about 65-75°C. The organic layer was separated and concentrated to about 5.3-5.9 L under vacuum, heptane (11.9 L) was added and the slurry was heated to about 55-65°C and stirred for about 2 hours. The reaction mixture was cooled to about 15-30°C over at least about 2 hours and then stirred at about 15-30°C for at least about 1 hour. The precipitate was filtered, washed with heptane (1.99 L) and dried. The filter cake was charged into reactor with ethyl acetate (5.31L, 8 vol) and heptane (2.65 L, 4 vol), cooled to about 15-30°C over at least about 2 hours and then stirred at about 15-30°C for at least about 1 hour. The precipitate was filtered, washed with heptane and dried to provide Compound I as a light yellow solid (648.4 gm, 89.4% yield, 99.4% purity by HPLC).

Step 4: Conversion of I to II

[0076] The reactor was charged with compound I (10 gm, 1 eq.), 110 mL ethanol was added and the reaction mixture was stirred. Concentrated hydrochloric acid (4.7 gm, 2 eq.) was slowly added to the reaction mixture while maintaining a temperature of about 30°C or less to form a clear solution. It was then filtered and washed with methanol (10 mL). It was again filtered and purified water (3 mL) was added to it at about 28-32°C. The mixture was stirred at about 28-32°C for 1-3 hours and filtered, purified water (177 mL) was added to it at about 25-32°C. The reaction mixture was cooled at about 0-7 °C and stirred for at least about 2 hours. Optionally, seed crystals of compound II can be added in this step. The solids were filtered, rinsed with acool (0-5°C) mixture of methanol (6 mL) and MTBE (24 mL), and with cool (0-5°C) MTBE (30 mL). The product was dried to provide Compound II (90% yield).

PATENT

WO2016179415,

PATENT

WO2008063888,

PATENT

WO2013142427, claiming use of pexidartinib for treating diseases eg Hodgkins disease, leukemia, muscular dystrophy and glaucoma.

PATENTS

US20152655862015-09-24COMPOUNDS MODULATING C-FMS AND/OR C-KIT ACTIVITY AND USES THEREFOR

US20142433652014-08-28COMPOUNDS MODULATING C-FMS AND/OR C-KIT ACTIVITY AND USES THEREFOR

US87227022014-05-13Compounds modulating c-fms and/or c-kit activity and uses therefor

US20140458402014-02-13COMPOUNDS AND METHODS FOR KINASE MODULATION, AND INDICATIONS THEREFOR

US20132742592013-10-17KINASE MODULATION AND INDICATIONS THEREFOR

US84047002013-03-26Compounds modulating c-fms and/or c-kit activity and uses therefor

US20112304822011-09-22COMPOUNDS MODULATING C-FMS AND/OR C-KIT ACTIVITY

US78930752011-02-22Compounds modulating c-fms and/or c-kit activity and uses therefor

//////1029044-16-3, Pexidartinib , PLX-3397, PHASE3

FC(F)(F)c1ccc(cn1)CNc2ccc(cn2)Cc4cnc3ncc(Cl)cc34

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Company	Theravance Biopharma Inc.
Description	Glycopeptide cephalosporin heterodimer antibiotic
Molecular Target
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Therapeutic Modality	Small molecule: Combination

Latest Stage of Development	Phase I
Standard Indication	Gram-negative bacterial infection
Indication Details	Treat Gram-positive bacterial infections

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Figure 2. Synthesis of genistein via deoxybenzoin route or chalcone route. 10

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Gilteritinib fumarate

Gilteritinib fumarate [USAN]

RN: 1254053-84-3

UNII: 5RZZ0Z1GJT

2-Pyrazinecarboxamide, 6-ethyl-3-((3-methoxy-4-(4-(4-methyl-1-piperazinyl)-1-piperidinyl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)-, (2E)-2-butenedioate (2:1)

Astellas Inititaties Phase 3 Registration Trial of gilteritinib (ASP2215) in Relapsed or Refractory Acute Myeloid Leukemia Patients

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Discovery and Structure−Activity Relationship of 3-Methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide (APD791): A Highly Selective 5-Hydroxytryptamine_2A Receptor Inverse Agonist for the Treatment of Arterial Thrombosis