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AM 2394

June 6, 2016 10:05 am / Leave a comment

AM 2394

1-(6′-(2-hydroxy-2-methylpropoxy)-4-((5-methylpyridin-3-yl)oxy)-[3,3′-bipyridin]-6-yl)-3-methylurea

Urea, N-[6′-(2-hydroxy-2-methylpropoxy)-4-[(5-methyl-3-pyridinyl)oxy][3,3′-bipyridin]-6-yl]-N‘-methyl-

CAS 1442684-77-6
Chemical Formula: C22H25N5O4
Exact Mass: 423.1907

Array Biopharma Inc., Amgen Inc. INNOVATORS

AM-2394 is a potent and selective Glucokinase agonist (GKA), which catalyzes the phosphorylation of glucose to glucose-6-phosphate. AM-2394 activates GK with an EC50 of 60 nM, increases the affinity of GK for glucose by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an ob/ob mouse model of diabetes

Type 2 diabetes mellitus (T2DM) is a disease characterized by elevated plasma glucose in the presence of insulin resistance and inadequate insulin secretion. Glucokinase (GK), a member of the hexokinase enzyme family, catalyzes the phosphorylation of glucose to glucose-6-phosphate in the presence of ATP.

Glucokioase i exok ase IV or D> is a glycolytic enssyiris that plays, an importaat. role irt blood sugar regulation .related to glucose utifeattoti a»d metabolism in the liver and pancreatic beta ^•cells. Serving as a glucose sessor, gtoeokiuase controls lasma glucose, levels. Glucokinaae plays a doal rob in .reducing plasma glucose levels; glucose-mediated activation of the en¾ymc in hepatocytes facilitates hepatic giocose npiafcc aad glycogen synthesis, while that la pancreatic beta ceils ultimately induces ins lin seeretio«. Both of these effects in turn reduce plasma glucose levels.

Clinical evidence has shown that, glueokitiase variants with, decreased, and increased activities are associated with mature easel, diabetes of the y ung { O0Y2) and persistent: hyperinsul nemic hypoglycemia &( infancy (PHHI), respectively. lso, aoo n.sulin dependent diabetes rneilitos (NIDDM) patients have been reported to have inappropriately lo giueokaiase activity; Ftirtherrnare. overexpressioa of glucokiuase it* dietary or gesetie animal models of diabetes either prevents, aoKiiorafes, or reverses the progress of pathological. symptoms in the disease. For these reasons, compounds that activate gfecokiaase have been sought by the pitasaaceatjeai liidustry.

International patent application, Publication No. WO 2 7/OS3345, which was published on May 10, 200?, discloses as giocokinase act ators certain 2-an«.aopyridiiie derivatives bearing at the 3 -position a meihyieneoxy-dkrked aromatic group a d on. the ammo group a heteroaryl ring, such as dna/oly! or i A4-lmadiazoiyl

it has .now been found that pyridyl ureas are useful as glneokirtase activators. Cettain of these •compounds have been, found to have an outstanding combination of properties that especially adapts them, for oral use to control plasma glucose levels.

Novel Series of Potent Glucokinase Activators Leading to the Discovery of AM-2394

Paul J. Dransfield^*^†, ^{ET AL}

^† Departments of Therapeutic Discovery, Metabolic Disorders, and Pharmacokinetics and Drug Metabolism, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States

^‡ Departments of Metabolic Disorders, Comparative Biology and Safety Sciences and Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States

^§ Array BioPharma Inc., 3200 Walnut Street, Boulder, Colorado 80301, United States

ACS Med. Chem. Lett., Article ASAP

DOI: 10.1021/acsmedchemlett.6b00140

http://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.6b00140

*E-mail: pdransfi@amgen.com.

Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate. We present the structure–activity relationships leading to the discovery of AM-2394, a structurally distinct GKA. AM-2394 activates GK with an EC₅₀ of 60 nM, increases the affinity of GK for glucose by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an ob/ob mouse model of diabetes.

PATENT

WO 2013086397

http://www.google.com/patents/WO2013086397A1?cl=en

COPYING ERROR

Example. 1734 t¾^Jtiyi¾rea

Step A: In 100 mL of DMA were corafeiaed 1 ^545miSO- -ll«omp ridinr2-yl)-3-i«e hir8a- (17.5 g, 70,5 ii!-!to!). 5-o:ieS:t}yI yiidlii~3- ). (9,24 g, S4.7 ΪΗΪΪΪΟ!}, sad CO · (10.1 g, 77.6 mmo!) mid heated to 90 *C for 5 days. After that time, the reaction was om lete a d to it was added water arid DCM and stirred vigorously for 3 hr. The resulting solid was isolated via vacuum .filtratiott nd the cake was wasted mill rater and DCM. The DCM in tli aqueous rime was dried vdth a stream of aidogeji aad vigorous sbrriug. Use resulting solid was then collected via vacuum filtration aad these solids were

Stirred vig rousl in f 0% MeOH irt EtOAc arid die res dtipg solid was colleeied. via vactiiars fiirfati m.

Trie two batches wen i coiiibiaed to yield I-(5-bmmo-4 5^»ie†fey pyiidin-3-yl xy)p Tidin-2- d 3~ metbySurea (I S J g, 5 3.7 om»)i, 76% yield).

S e .8: In 2 niL ofc ioxane

yI) iyridMJ-2-yios:y)pf¾ps3i-2-oI (0,098 g, 0.33 «ΜΠΟΪ), ^“ -i5-bs¾tao-4-{5-a3fidiy I py f idia-3 – ylosy)f5yridia-2-yl)-3-raethyl«rea (0.075 g, 0.22 tn ol._. t, and.2M poiass.ua» carbonate (0.33 ml, 0.67 m oi} artd tfets was s parged wi h At .for 10 mia before PdC§4dppl)*DCM (0.01 g g, 0.022 msttol) was added and dre reae!io a was sparged for aaotber 5 ma-, ir efore a was sealed and heated to 100 oversight The react! art was then loaded directly onto s ilica gel (50% acetone to PCM w4i. }%

MH40H) to afford i – (6′-(2diydioxy-2ⁱ-H5eth:ylpropCis:y) -4-{ 5″i:t re th y Ipy r i d i rt -3- io s y ) -3 ,3 ^: -bipyr id i rt -6- yl)-3-aie5¾ylt)rea φ.? 42 , 0.096 m ol, 43 % yield). ^!1 1 HMR (400 Mife, CDCij) 3 ppm 9.06 is,. !H),

S.33 is, 1H>, 8,27 (rs 2H), 8. Π (s, I H)_: K. (s, IHU 82 (dd, j-S.fi, 5.9 H HI), 1.21 (S !H), 6,«8

(d, Hz, i i i ). 6. ,4 (s_:. m>, 4.25 (s, 2H), 2,87 (dj =4,3 Hz„ 3H) 2,37 (s, 3H>. 1 .33 is, <SH). Mass speetram (apci) tar/, ^: – 423.9 (M÷H).

REFERENCES

Novel Series of Potent Glucokinase Activators Leading to the Discovery of AM-2394
Paul J. Dransfield, Vatee Pattaropong, Sujen Lai, Zice Fu, Todd J. Kohn, Xiaohui Du, Alan Cheng, Yumei Xiong, Renee Komorowski, Lixia Jin, Marion Conn, Eric Tien, Walter E. DeWolf Jr., Ronald J. Hinklin, Thomas D. Aicher, Christopher F. Kraser, Steven A. Boyd, Walter C. Voegtli, Kevin R. Condroski, Murielle Veniant-Ellison, Julio C. Medina, Jonathan Houze, and Peter Coward
Publication Date (Web): May 23, 2016 (Letter)
DOI: 10.1021/acsmedchemlett.6b00140

/////////Glucokinase activator, GKA, AM-2394, 1442684-77-6, AM 2394, Amgen

O=C(NC)NC1=CC(OC2=CC(C)=CN=C2)=C(C3=CC=C(OCC(C)(O)C)N=C3)C=N1

Obeticholic acid

June 3, 2016 10:15 am / Leave a comment

Obeticholic acid

Obeticholic acid; 6-ECDCA; INT-747; 459789-99-2; 6-Ethylchenodeoxycholic acid; 6alpha-Ethyl-chenodeoxycholic acid;

(4R)-4-[(3R,5S,6R,7R,8S,9S,10S,13R,14S,17R)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid


Molecular Formula:	C₂₆H₄₄O₄
Molecular Weight:	420.62516 g/mol

A farnesoid X receptor (FXR) agonist potentially for treatment of primary biliary cirrhosis and nonalcoholic steatohepatitis.

6-ECDCA; DSP-1747; INT-747

CAS No.459789-99-2

Obeticholic acid.png

Obeticholic acid (abbreviated to OCA), is a semi-synthetic bile acid analogue which has the chemical structure 6α-ethyl-chenodeoxycholic acid. It has also been known as INT-747. It is undergoing development as a pharmaceutical agent for severalliver diseases and related disorders. Intercept Pharmaceuticals Inc. (NASDAQ symbol ICPT) hold the worldwide rights to develop OCA outside Japan and China, where it is licensed to Dainippon Sumitomo Pharma.^[2]

REVIEW
INT-747(Obeticholic acid; 6-ECDCA) is a potent and selective FXR agonist(EC50=99 nM) endowed with anticholestatic activity. IC50 value: 99 nM(EC50) [1] Target: FXR agonist in vitro: The exposure of rat hepatocytes to 1 microM 6-ECDCA caused a 3- to 5-fold induction of small heterodimer partner (Shp) and bile salt export pump (bsep) mRNA and 70 to 80% reduction of cholesterol 7alpha-hydroxylase (cyp7a1), oxysterol 12beta-hydroxylase (cyp8b1), and Na(+)/taurocholate cotransporting peptide (ntcp) [2]. in vivo: In vivo administration of 6-ECDCA protects against cholestasis induced by E(2)17alpha [2]. high salt (HS) diet significantly increased systemic blood pressure. In addition, HS diet downregulated tissue DDAH expression while INT-747 protected the loss in DDAH expression and enhanced insulin sensitivity compared to vehicle controls [3]. Rats were gavaged with INT-747 or vehicle during 10 days after bile-duct ligation and then were assessed for changes in gut permeability, BTL, and tight-junction protein expression, immune cell recruitment, and cytokine expression in ileum, mesenteric lymph nodes, and spleen. After INT-747 treatment, natural killer cells and interferon-gamma expression markedly decreased, in association with normalized permeability selectively in ileum (up-regulated claudin-1 and occludin) and a significant reduction in BTL [4].

REFERENCES

[1]	Verbeke L, et al. The FXR Agonist Obeticholic Acid Prevents Gut Barrier Dysfunction and Bacterial Translocation in Cholestatic Rats. Am J Pathol. 2015 Feb;185(2):409-19.
[2]	Ghebremariam YT, et al. FXR agonist INT-747 upregulates DDAH expression and enhances insulin sensitivity in high-salt fed Dahl rats. PLoS One. 2013 Apr 4;8(4):e60653.
[3]	Fiorucci S, et al. Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid X receptor ligand, in estrogen-induced cholestasis. J Pharmacol Exp Ther. 2005 May;313(2):604-12.
[4]	Pellicciari R, et al. 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 2002 Aug 15;45(17):3569-72.

Invention and development

The natural bile acid, chenodeoxycholic acid, was identified in 1999 as the most active physiological ligand for the farnesoid X receptor (FXR), which is involved in many physiological and pathological processes. A series of alkylated bile acid analogues were designed, studied and patented by Roberto Pellicciari and colleagues at the University of Perugia, with 6α-ethyl-chenodeoxycholic acid emerging as the most highly potent FXR agonist.^[3] FXR-dependent processes in liver and intestine were proposed as therapeutic targets in human diseases.^[4] Obeticholic acid is the first FXR agonist to be used in human drug studies.

Clinical studies

OCA is undergoing development in phase 2 and 3 studies for specific liver and gastrointestinal disorders.^[5]

Primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is an auto-immune, inflammatory liver disease which produces bile duct injury, fibrosis, cholestasisand eventual cirrhosis. It is much more common in women than men and can cause jaundice, itching (pruritus) and fatigue.Ursodeoxycholic acid therapy is beneficial, but the disease often progresses and may require liver transplantation.^[6] Animal studies suggested that treatment with FXR agonists should be beneficial in cholestatic diseases such as PBC.^[7] OCA at doses between 10 mg and 50 mg was shown to provide significant biochemical benefit, but pruritus was more frequent with higher doses.^[8]^[9] The results of a randomized, double-blind phase 3 study of OCA, 5 mg or 10 mg, compared to placebo (POISE) were presented in April 2014, and showed that the drug met the trial’s primary endpoint of a significant reduction in serum alkaline phosphatase, abiomarker predictive of disease progression, liver transplantation or death.^[10]

Nonalcoholic steatohepatitis (NASH)

Non-alcoholic steatohepatitis is a common cause of abnormal liver function with histological features of fatty liver, inflammation andfibrosis. It may progress to cirrhosis and is becoming an increasing indication for liver transplantation. It is increasing in prevalence. OCA is proposed to treat NASH.^[11] A phase 2 trial published in 2013 showed that administration of OCA at 25 mg or 50 mg daily for 6 weeks reduced markers of liver inflammation and fibrosis and increased insulin sensitivity.^[12]

The Farnesoid X Receptor Ligand Obeticholic Acid in Nonalcoholic Steatohepatitis Treatment (FLINT) trial, sponsored by NIDDK, was halted early in January 2014, after about half of the 283 subjects had completed the study, when a planned interim analysis showed that a) the primary endpoint had been met and b) lipid abnormalities were detected and arose safety concerns. Treatment with OCA (25 mg/day for 72 weeks) resulted in a highly statistically significant improvement in the primary histological endpoint, defined as a decrease in the NAFLD Activity Score of at least two points, with no worsening of fibrosis. 45% (50 of 110) of the treated group had this improvement compared with 21% (23 of 109) of the placebo-treated controls.^[13] However concerns about longterm safety issues such as increased cholesterol and adverse cardiovascular events may warrant the concomitant use of statins in OCA-treated patients.^[14]

Portal hypertension

Animal studies suggest that OCA improves intrahepatic vascular resistance and so may be of therapeutic benefit in portal hypertension.^[15] An open label phase 2a clinical study is under way.

Bile acid diarrhea

Bile acid diarrhea (also called bile acid malabsorption) can be secondary to Crohn’s disease or be a primary condition. Reduced median levels of FGF19, an ileal hormone that regulates increased hepatic bile acid synthesis, have been found in this condition.^[16] FGF19 is potently stimulated by bile acids and especially by OCA.^[17] A proof of concept study of OCA (25 mg/d) has shown clinical and biochemical benefit.^[18]

SYNTHESIS

CN 105541953

Take 10g of austempered cholic acid 89.6% purity crude (single hetero greater than 2%), 3 times its weight of acetone and added to their 20% by weight of triethylamine was added, was heated at reflux for 2h, cooled slowly to 10 ° C, the precipitated crystals were filtered to give Obey acid organic amine salt crystals.

Acidification [0020] The organic amine salts Obey acid crystals were dissolved with purified water after 10wt% by mass percentage to the PH value of 2.0 with dilute hydrochloric acid, filtered and dried to give purified Obey acid.

[0021] The purified Obey acid ethyl acetate dissolved by heating and then cooling to 20 ° C, the precipitated crystals were filtered and dried to obtain a purity of 98.7% recrystallization Obey acid (single hetero less than 0.1%), recovery was 84.5%.

PATENT

WO 2016045480

Obey acid (as shown in formula I) is a semi-synthetic chenodeoxycholic acid derivative, for the treatment of high blood pressure, the portal vein and liver diseases, including primary biliary cirrhosis, bile acid diarrhea, non-alcoholic steatohepatitis. Obey acid through activation of FXR receptors play a role, FXR is a nuclear receptor, is expressed mainly in the liver, intestine, kidney, and it can be adjusted with acids fat and carbohydrate metabolism related gene expression in bile, also regulate immune response. FXR activation can inhibit the synthesis of bile acids, bile acids prevent excessive accumulation of toxic reactions caused.

WO2002072598 debuted Obey acid preparation method (shown below), which in strong alkaline conditions to give compound VII by alkylation with ethyl iodide compound VI directly, through reducing compound VII prepared and carboxy deprotection Obey acid. However, due to direct alkylation with ethyl iodide poor selectivity and yield is too low, the synthesis process is difficult to achieve amplification synthesis.

Obey bile acid synthesis (WO2002072598)

WO2006122977 above synthesis process has been improved (see below), the process by the silicon compound IX into protected enol compound X, compound X and acetaldehyde after dehydration condensation to give compound Vb, after compound Vb in alkaline conditions under palladium on carbon hydrogenation to give compound XI, after a carbonyl compound XI reduction system Obey acid.

Obey bile acid synthesis (WO2006122977)

The synthetic process can be achieved, although the enlarged combined, however, the compound Vb produce large amounts of byproducts under strongly alkaline conditions palladium on carbon hydrogenation process for preparing high temperature and strong alkaline compound XI during this step leading to the separation of income a lower rate (about 60%), low yield of this step may be due to compound Vb and XI in unprotected hydroxy dehydration occurs under strongly basic (30% NaOH) and high temperature (95-105 ℃) conditions side effects caused.

synthesis of bile acids Obey,

Obey bile acid synthesis route is as follows:

PATENT

CN 105175473

According to Obey acid 6 was prepared in the form of C Patent Document W02013192097A1 reaction of Example 1, as follows:

The 3 a – hydroxy -6 a – ethyl-7-keto -5 P – 24-oic acid (. 86g, 205 4mmol), water (688mL) and 50% (w / w) hydrogen sodium hydroxide solution (56. 4mL) and the mixture of sodium borohydride (7. 77g, 205. 4mmol) in a mixture of 50% (w / w) sodium hydroxide solution (1.5 mL of) and water (20 mL) in 90 ° in C to 105 ° C reaction. Was heated with stirring under reflux for at least 3 hours, the reaction was completed, the reaction solution was cooled to 80 ° C. Between 30 ° C at 50 ° C of citric acid (320. 2g, anhydrous), a mixture of n-butyl acetate (860 mL of) and water (491mL) to ensure an acidic pH of the aqueous phase was separated. Evaporation of the organic phase was distilled to give the residue was diluted with n-butyl acetate, slowly cooled to 15 ° C to 20 ° C, centrifugation. The crude product was crystallized from n-butyl acetate. After Obey acid isolated by n-butyl acetate (43mL, 4 times), dried samples were dried at 80 ° C under vacuum. To give 67. 34g (77. 9%) crystalline form C Obey acid.

References

Gioiello, Antimo; Macchiarulo, Antonio; Carotti, Andrea; Filipponi, Paolo; Costantino, Gabriele; Rizzo, Giovanni; Adorini, Luciano; Pellicciari, Roberto (April 2011). “Extending SAR of bile acids as FXR ligands: Discovery of 23-N-(carbocinnamyloxy)-3α,7α-dihydroxy-6α-ethyl-24-nor-5β-cholan-23-amine”. Bioorganic & Medicinal Chemistry 19 (8): 2650–2658.doi:10.1016/j.bmc.2011.03.004.
Wall Street Journal. “A $4 Billion Surprise for 45-Person Biotech”. Retrieved10 January 2014.
Pellicciari R, Fiorucci S, Camaioni E, Clerici C, Costantino G, Maloney PR, Morelli A, Parks DJ, Willson TM (August 2002). “6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity”. J. Med. Chem. 45(17): 3569–72. doi:10.1021/jm025529g. PMID 12166927.
Rizzo G, Renga B, Mencarelli A, Pellicciari R, Fiorucci S (September 2005). “Role of FXR in regulating bile acid homeostasis and relevance for human diseases”. Curr. Drug Targets Immune Endocr. Metabol. Disord. 5 (3): 289–303. doi:10.2174/1568008054863781.PMID 16178789.
“ClinicalTrials.gov”.
Hirschfield GM, Gershwin ME (January 2013). “The immunobiology and pathophysiology of primary biliary cirrhosis”. Annu Rev Pathol 8: 303–30. doi:10.1146/annurev-pathol-020712-164014. PMID 23347352.
Jump up^ Lindor, KD (May 2011). “Farnesoid X receptor agonists for primary biliary cirrhosis”.Current opinion in gastroenterology 27 (3): 285–8.doi:10.1097/MOG.0b013e32834452c8. PMID 21297469.
Jump up^ Fiorucci S, Cipriani S, Mencarelli A, Baldelli F, Bifulco G, Zampella A (August 2011). “Farnesoid X receptor agonist for the treatment of liver and metabolic disorders: focus on 6-ethyl-CDCA”. Mini Rev Med Chem 11 (9): 753–62. doi:10.2174/138955711796355258.PMID 21707532.
Jump up^ Hirschfield GM, Mason A, Luketic V, Lindor K, Gordon SC, Mayo M, Kowdley KV, Vincent C, Bodhenheimer HC, Parés A, Trauner M, Marschall HU, Adorini L, Sciacca C, Beecher-Jones T, Castelloe E, Böhm O, Shapiro D (2015). “Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid”.Gastroenterology 148 (4): 751–61.e8. doi:10.1053/j.gastro.2014.12.005.PMID 25500425.
Jump up^ Intercept Pharma. “Press release: Intercept Announces Positive Pivotal Phase 3 POISE Trial Results”. Retrieved March 27, 2014.
Jump up^ Adorini L, Pruzanski M, Shapiro D (September 2012). “Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis”. Drug Discov. Today 17 (17–18): 988–97.doi:10.1016/j.drudis.2012.05.012. PMID 22652341.
Jump up^ Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, Adorini L, Sciacca CI, Clopton P, Castelloe E, Dillon P, Pruzanski M, Shapiro D (September 2013). “Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease”. Gastroenterology 145 (3): 574–82.e1.doi:10.1053/j.gastro.2013.05.042. PMID 23727264.
Jump up^ Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, Chalasani N, Dasarathy S, Diehl AM, Hameed B, Kowdley KV, McCullough A, Terrault N, Clark JM, Tonascia J, Brunt EM, Kleiner DE, Doo E (2015). “Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial”. Lancet 385 (9972): 956–65.doi:10.1016/S0140-6736(14)61933-4. PMID 25468160.
Jump up^ http://www.thestreet.com/story/12714549/1/intercept-pharma-government-scientists-spar-over-negative-safety-of-liver-drug-emails-show.html?puc=yahoo&cm_ven=YAHOO
Verbeke L, Farre R, Trebicka J, Komuta M, Roskams T, Klein S, Vander Elst I, Windmolders P, Vanuytsel T, Nevens F, Laleman W (November 2013). “Obeticholic acid, a farnesoid-X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats”. Hepatology 59 (6): :2286–98. doi:10.1002/hep.26939. PMID 24259407.
Walters JR, Tasleem AM, Omer OS, Brydon WG, Dew T, le Roux CW (November 2009). “A new mechanism for bile acid diarrhea: defective feedback inhibition of bile acid biosynthesis”. Clin. Gastroenterol. Hepatol. 7 (11): 1189–94.doi:10.1016/j.cgh.2009.04.024. PMID 19426836.
Zhang JH, Nolan JD, Kennie SL, Johnston IM, Dew T, Dixon PH, Williamson C, Walters JR (May 2013). “Potent stimulation of fibroblast growth factor 19 expression in the human ileum by bile acids”. Am. J. Physiol. Gastrointest. Liver Physiol. 304 (10): G940–8.doi:10.1152/ajpgi.00398.2012. PMC 3652069. PMID 23518683.
Walters JR, Johnston IM, Nolan JD, Vassie C, Pruzanski ME, Shapiro DA (January 2015). “The response of patients with bile acid diarrhoea to the farnesoid X receptor agonist obeticholic acid”. Aliment. Pharmacol. Ther. 41 (1): 54–64.doi:10.1111/apt.12999. PMID 25329562.

External links

“Intercept pharmaceuticals”.
NashBiotechs Several articles on drug candidates in NASH

Patent ID	Date	Patent Title
US8546365	2013-10-01	Bile acid derivatives as FXR ligands for the prevention or treatment of FXR-mediated diseases or conditions
US8377916	2013-02-19	Steroids as agonists for FXR
US8058267	2011-11-15	STEROIDS AS AGONISTS FOR FXR
US7994352	2011-08-09	Process for Preparing 3a(Beta)-7a(Beta)-Dihydroxy-6a(Beta)-Alkyl-5Beta-Cholanic Acid
US7932244	2011-04-26	Bile acid derivatives as FXR ligands for the prevention or treatment of FXR-mediated diseases or conditions
US7786102	2010-08-31	Steroids as agonists for FXR
US2009062526	2009-03-05	NOVEL METHOD OF SYNTHESIZING ALKYLATED BILE ACID DERIVATIVES
US7138390	2006-11-21	Steroids as agonists for fxr
US2005107475	2005-05-19	Methods of using farnesoid x receptor (frx) agonists

Patent ID	Date	Patent Title
US2016074419	2016-03-17	Preparation and Uses of Obeticholic Acid
US2015359805	2015-12-17	Bile Acid Derivatives as FXR Ligands for the Prevention or Treatment of FXR-Mediated Diseases or Conditions
US2015166598	2015-06-18	Steroids as Agonists for FXR
US2014371190	2014-12-18	Farnesoid X receptor modulators
US2014186438	2014-07-03	COMPOSITIONS COMPRISING EPA AND OBETICHOLIC ACID AND METHODS OF USE THEREOF
US2014148428	2014-05-29	Treatment of Pulmonary Disease
US2014057886	2014-02-27	Bile Acid Derivatives as FXR Ligands for the Prevention or Treatment of FXR-Mediated Diseases or Conditions
US2014024631	2014-01-23	Steroids as Agonists for FXR
US2013345188	2013-12-26	Preparation and Uses of Obeticholic Acid
US8546365	2013-10-01	Bile acid derivatives as FXR ligands for the prevention or treatment of FXR-mediated diseases or conditions

Obeticholic acid
Systematic (IUPAC) name

(3α,5β,6α,7α)-6-Ethyl-3,7-dihydroxycholan-24-oic acidOR (4R)-4-[(3R,5S,6R,7R,8S,9S,10S,13R,14S,17R)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid
Clinical data
Routes of administration	Oral
Legal status
Legal status	Investigational New Drug
Identifiers
CAS Number	459789-99-2
ATC code	A05AA04 (WHO)
PubChem	CID 447715
IUPHAR/BPS	3435
ChemSpider	394730
UNII	0462Z4S4OZ
KEGG	C15636
ChEMBL	CHEMBL566315
Synonyms	6α-ethyl-chenodeoxycholic acid; INT-747
Chemical data
Formula	C₂₆H₄₄O₄
Molar mass	420.62516 g/mol

/////////6-ECDCA, DSP-1747, INT-747, 459789-99-2, Obeticholic acid

CC[C@@H]1[C@@H]2C[C@@H](CC[C@@]2([C@H]3CC[C@]4([C@H]([C@@H]3[C@@H]1O)CC[C@@H]4[C@H](C)CCC(=O)O)C)C)O

CCC1C2CC(CCC2(C3CCC4(C(C3C1O)CCC4C(C)CCC(=O)O)C)C)O

Ladostigil

June 2, 2016 11:49 am / Leave a comment

Ladostigil, TV-3,326

(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate

(3R)-3-(Prop-2-ynylamino)indan-5-yl ethyl(methyl)carbamate; R-CPAI

Carbamic acid, ethylmethyl-, (3R)-2,3-dihydro-3-(2-propynylamino)-1H-inden-5-yl ester

Condition(s): Mild Cognitive Impairment
U.S. FDA Status: Mild Cognitive Impairment (Phase 2)
Company: Avraham Pharmaceuticals Ltd

Target Type: Cholinergic System

CAS No:	209349-27-4
Synonyms:	Ladostigil, TV-3326, UNII-SW3H1USR4Q
Molecular Weight:	272.346 g/mol

Chemical Formula:	C16-H20-N2-O2

IUPAC Name:	(3R)-3-(Prop-2-ynylamino)indan-5-yl ethyl(methyl)carbamate N-Propargyl-(3R)-aminoindan-5-yl) ethyl methyl carbamate

Ladostigil tartrate Structure

CAS 209394-46-7, Ladostigil tartrate

N-Ethyl-N-methylcarbamic acid 3(R)-(2-propynylamino)-2,3-dihydro-1H-inden-5-yl ester L-tartrate

In 2010, ladostigil tartrate was licensed by Technion Research & Development Foundation and Yissum to Avraham for the treatment of Alzheimer’s disease and other neurogenerative diseases.

Ladostigil (TV-3,326) is a novel neuroprotective agent being investigated for the treatment of neurodegenerative disorders likeAlzheimer’s disease, Lewy body disease, and Parkinson’s disease.^[1] It acts as a reversible acetylcholinesterase andbutyrylcholinesterase inhibitor, and an irreversible monoamine oxidase B inhibitor, and combines the mechanisms of action of older drugs like rivastigmine and rasagiline into a single molecule.^[2]^[3] In addition to its neuroprotective properties, ladostigil enhances the expression of neurotrophic factors like GDNF and BDNF, and may be capable of reversing some of the damage seen in neurodegenerative diseases via the induction of neurogenesis.^[4] Ladostigil also has antidepressant effects, and may be useful for treating comorbid depression and anxiety often seen in such diseases as well.^[5]^[6]

Ladostigil [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate] is a dual acetylcholine-butyrylcholineesterase and brain selective monoamine oxidase (MAO)-A and -B inhibitor in vivo (with little or no MAO inhibitory effect in the liver and small intestine), intended for the treatment of dementia co-morbid with extrapyramidal disorders and depression (presently in a Phase IIb clinical study). This suggests that the drug should not cause a significant potentiation of the cardiovascular response to tyramine, thereby making it a potentially safer antidepressant than other irreversible MAO-A inhibitors. Ladostigil was shown to antagonize scopolamine-induced impairment in spatial memory, indicating that it can cause significant increases in rat brain cholinergic activity. Furthermore, ladostigil prevented gliosis and oxidative-nitrative stress and reduced the deficits in episodic and spatial memory induced by intracerebroventricular injection of streptozotocin in rats. Ladostigil was demonstrated to possess potent anti-apoptotic and neuroprotective activities in vitro and in various neurodegenerative rat models, (e.g. hippocampal damage induced by global ischemia in gerbils and cerebral oedema induced in mice by closed head injury). These neuroprotective activities involve regulation of amyloid precursor protein processing; activation of protein kinase C and mitogen-activated protein kinase signaling pathways; inhibition of neuronal death markers; prevention of the fall in mitochondrial membrane potential and upregulation of neurotrophic factors and antioxidative activity. Recent findings demonstrated that the major metabolite of ladostigil, hydroxy-1-(R)-aminoindan has also a neuroprotective activity and thus, may contribute to the overt activity of its parent compound. This review will discuss the scientific evidence for the therapeutic potential use of ladostigil in Alzheimer’s and Lewy Body diseases and the molecular signaling pathways that are considered to be involved in the biological activities of the drug

LADOSTIGIL

Recently, Yissum Research Development Company associated with the Hebrew University of Jerusalem announced that the University will use a portion of a $9 million dollar grant awarded to Avraham Pharmaceuticals, Pontifax, Clal Biotechnology Industries and Professor Marta Weinstock-Rosin to complete the Phase II efficacy trial in patients afflicted with Alzheimer’s disease.

The trial will be conducted over the course of 52 weeks and will involve the novel drug, Ladostigil. Ladostigil is a new comprehensive drug used to combat symptoms of Alzheimer’s, Parkinson’s, depression, and anxiety. The drug is deemed multi-functional because it addresses a host of neurodegenerative problems. Ladostigil is a brain-selective monoamine oxidase inhibitor (MAOI) that protects the neurons.

PATENT

US 20140243544 http://www.google.co.in/patents/US20140243544

PATENT

WO 2008074816

http://www.google.com/patents/WO2008074816A1?cl=en

Ethylmethyl carbamyl chloride (15.5 g, 127.57 mmol) was added to a stirred suspension of 6-hydroxy-1-indanone (17.2 g, 116.1 mmol) and potassium carbonate (31.8 g, 188 mmol) in acetonitrile (800 mL) at room temperature over a period of 15 minutes. The reaction mixture was heated to reflux and refluxed for 18 hours. The reaction mixture was cooled to ambient temperature, the solvent evaporated and the residue was diluted with water (250 mL) and extracted three times with toluene (250 mL). The combined organic phase was dried on MgSO and toluene was evaporated in a rotary evaporator. The crude crystalline product was purified by crystallization from 2-propanol (200 mL), collected by filtration, and dried under vacuum at 50° C. to afford the title compound (22 g, 81.5%).

1H NMR (300 MHz, CDCl₃) δ ppm 7.47-7.44 (2H, m, Ar), 7.36 (1H, dd, J 8.4 and 2.1, Ar), 3.52-3.37 (2H, m, NCH₂CH₃), 3.14-3.108 [2H, m, OCCH₂CH₂and incl. NCH₃(two rotamers), at 3.08 and 2.99 (3H, s, Me)], 2.74-2.71 (2H, m, OCCH₂CH₂) and 1.25 and 1.19 (two rotamers) (3H,two triplets, J 6.9). Mass Spectrum (FAB+) [MH⁺=234

Example 6(S)-Dimethyl-carbamic acid 3-prop-2-ynylamino-indan-5-yl ester

Methanesulfonyl anhydride (296 mg, 1.7 mmol) as a solution in dichloromethane (1.5 mL+0.5 mL) was added to a stirred solution of (R)-dimethyl-methyl-carbamic acid 3-hydroxy-indan-5-yl ester (188 mg, 0.8 mmol, product of example 1a) and triethylamine (0.47 mL, 3.4 mmol) in dichloromethane (2 mL) at −78° C. (external) over 10 minutes. The reaction was maintained at this temperature for 1 hour before propargylamine (1.20 mL, 17.0 mmol) was added. The reaction was allowed to warm slowly to room temperature overnight before being partitioned between ethyl acetate (20 mL) and ice-water (20 mL). The organic material was concentrated under reduced pressure to afford a brown oil which was partitioned between methyl tert-butyl ether (10 mL) and aqueous hydrochloric acid (1M, 10 mL). The aqueous layer was basified by addition of aqueous sodium hydroxide solution (2M, 16 mL) before being extracted with ethyl acetate (10 mL). This final organic extract was dried (MgSO₄), filtered and concentrated under reduced pressure to afford the title compound (175 mg, 80%). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.19 (1H, d, J 8, Ar), 7.09 (1H, d, J 2, Ar), 6.94 (1H, dd, J 8 and 2, Ar), 4.39 (1H, dd, J 6 and 6, CHNH), 3.54 (1H, Dd, J 17 and 3, NCHH), 3.49 (1H, Dd, J 16 and 3, HNCHH), 3.09 (3H, s, Me), 3.03-2.96 [4H, m, NCHCHH and Me incl. at 3.00 (3H, s, Me)], 2.83-2.75 (1H, m, NCHCHH), 2.48-2.39 (1H, m, NCHCH₂CHH), 2.25 (1H, t, J 2, ≡CH) and 1.92-1.83 (1H, m, NCHCH₂CHH). Analysis of this material by chiral LC indicated it to be 70% e.e.

Example 7b(R)-Ethyl-methyl-carbamic acid 3-prop-2-ynylamino-indan-5-yl ester (ladostigil)

The procedure of example 7a is repeated with (S)-ethyl-methyl-carbamic acid 3-hydroxy-indan-5-yl ester instead of (R)-ethyl-methyl-carbamic acid 3-hydroxy-indan-5-yl ester. The R-enantiomer is produced.

PAPER

Tetrahedron: Asymmetry (2012), 23(5), 333-338

http://www.sciencedirect.com/science/article/pii/S0957416612001334

Image for unlabelled figure

(R)-3-(Prop-2-ynylamino)-2,3-dihydro-1H-inden-5-yl ethyl(methyl)carbamate

C₁₆H₂₀N₂O₂

ee: 89%

(c 1.46, CHCl₃)

Source of chirality: the precursor

Absolute configuration: (R)

(R)-3-(Prop-2-ynylamino)-2,3-dihydro-1H-inden-5-yl ethyl(methyl)carbamate hemi((2R,3R)-2,3-dihydroxysuccinate)

C₃₆H₄₆N₄O₁₀

ee: 99%

(c1.95, CHCl₃)

Source of chirality: the precursor

Absolute configuration: (R,R,R)

Avraham Pharmaceuticals Announces Commencement of a Phase 2 Study of Ladostigil for the Treatment of MCI

Posted on May 17, 2012

Yaacov Michlin appointed Chairman of the Board and Dr. Yona Geffen appointed Chief Executive Officer

Yavne, Israel, May 17, 2012 — Avraham Pharmaceuticals Ltd. announced today the commencement of a Phase 2 clinical trial to evaluate the safety and efficacy of ladostigil in patients diagnosed with mild cognitive impairment (MCI). This 36-month, multi-centre, randomized, double-blind, placebo-controlled trial will include at least 200 patients in 16 centers in Europe and Israel.

In parallel, Avraham Pharmaceuticals has also completed the enrollment of 200 patients in a Phase 2 trial of ladostigil, a novel molecule for the treatment of mild to moderate Alzheimer’s disease. The Phase 2 study is a double-blind, closed-label, placebo-controlled trial taking place at 20 sites in five countries across Europe. In January 2012, the Company performed an interim analysis of this Phase 2 trial, which indicated that the drug is safe and well tolerated, as well as shows a positive trend toward efficacy. Final results of the 26-week trial are expected in the fourth quarter of 2012.

The Company also announced today that it has appointed Yaacov Michlin, CEO of Yissum Research Development Company of the Hebrew University of Jerusalem Ltd., the technology transfer arm of the University, as Chairman of the Board and Yona Geffen, Ph.D., as Chief Executive Officer.

“We strongly believe in ladostigil and are confident that Yona’s background and extensive experience in developing therapies for neurological disorders and neurodegenerative diseases renders her the perfect choice to lead Avraham,” said Yaacov Michlin, Chairman of Avraham Pharmaceuticals and Chief Executive Officer of Yissum. “In further researches performed by Prof. Weinstock-Rosin, ladostigil has showed promise also for the treatment of MCI in addition to Alzheimer’s disease. We are pleased that another Phase 2 clinical trial in patients with MCI has begun in parallel, and look forward to the final results of the Phase 2 study for the treatment of Alzheimer’s disease expected at the end of this year.”

“I am delighted to lead Avraham in these exciting times for the company, as we advance ladostigil in 2 Phase 2 clinical trials simultaneously. We believe that this unique drug candidate has the potential to transform the treatment of various neurodegenerative diseases,” said Dr. Yona Geffen, Avraham Pharmaceuticals Chief Executive Officer.

Dr. Yona Geffen joined Avraham Pharmaceuticals in January 2011 as Senior Vice President of Clinical Affairs and Chief Operating Officer. Dr. Geffen has more than 12 years of experience in the field of drug development in biopharmaceutical companies. Prior to Avraham, she was Executive Drug Development Director at BiolineRx (NASDAQ: BLRX). Before that, Dr. Geffen was a project manager at Proneuron Biotechnologies. Dr. Geffen received her Ph.D. from Ben Gurion University in Beer Sheva, Israel. She also holds an M.Sc. in business management.

Yaacov Michlin has been CEO of Yissum since 2009. Prior to Yissum, Mr. Michlin spent over a decade in leading and assisting pharmaceutical, hi-tech and biomedical companies in various technology commercialization deals, licensing agreements, capital raising activities, partnerships, mergers and acquisitions. Michlin holds a Bachelor of Law and Economics cum laude, and a Master of Law all from Bar-Ilan University, Ramat Gan, Israel. In addition, he has an MBA cum laude from the Technion Israel Institute of Technology, Haifa, Israel.

About Ladostigil

Ladostigil is a novel cholinesterase and brain-selective monoamine oxidase inhibitor, and neuroprotective agent for the treatment of Alzheimer’s disease, mild cognitive impairment and other neurodegenerative diseases. The drug, which was exclusively licensed to Avraham Pharmaceuticals by Yissum Research Development Company Ltd., and by the Technion Research and Development Foundation Ltd. (TRDF), has proven to be safe and well tolerated in Phase 1 and Phase 2 clinical trials. Like other cholinesterase inhibitors currently on the market, ladostigil targets symptomatic relief in Alzheimer’s disease patients. But unlike these drugs, ladostigil, which also causes brain selective inhibition of monoamine oxidase (MAO) provides the potential to improve the behavioral and psychological symptoms of dementia such as depression and anxiety. Moreover, ladostigil has the potential to slow progression of clinical symptoms of Alzheimer’s disease for sustained periods of time and to modify the pathology associated with the disease. In addition, the neuroprotective activity of ladostigil provides a drug candidate that may have the potential to slow progression to Alzheimer’s disease in patients diagnosed with MCI. This potential has been amply demonstrated in animal models, especially in studies of ageing rats.

Ladostigil was designed by Professor Marta Weinstock-Rosin of the Hebrew University of Jerusalem, inventor of Exelon® and Professor Moussa B.H. Youdim of the Technion Israel Institute of Technology, inventor of Azilect®. The drug substance was first synthesized by Professor Michael Chorev of the Hebrew University, who is now based at Harvard University. All three distinguished scientists act as scientific advisors to Avraham Pharmaceuticals.

About Alzheimer’s Disease

Alzheimer’s disease is the most common cause of dementia worldwide, affecting about one in 20 people 65 years of age or older, accounting for 60-80% of dementia cases. In 2010, 5.4 million people were affected by Alzheimer’s disease in the U.S., where it is the 6th leading cause of death. In Europe, more than 6 million are living with the disease. Approximately half of Alzheimer’s patients also suffer from depression, and up to 40% also exhibit Parkinson-like symptoms.

About Mild Cognitive Impairment

Mild cognitive impairment (MCI) is a syndrome defined as an intermediate stage between the expected cognitive decline of normal aging and the more pronounced decline of dementia. It involves problems with memory, language, thinking and judgment that are greater than typical age-related changes. Although MCI can present with a variety of symptoms, when memory loss is the predominant symptom it is termed “amnestic MCI” and is frequently seen as a prodromal stage of Alzheimer’s disease. Prevalence in population-based epidemiological studies ranges from 3% to 19% in adults older than 65 years. There is no proven treatment or therapy for MCI.

About Avraham Pharmaceutical

Founded in 2010, Avraham Pharmaceuticals has raised more than $12 million to advance the development of its unique, multi-functional drug substance, ladostigil, currently undergoing two Phase 2 clinical trials for the treatment of Alzheimer’s disease and mild cognitive impairment. The Company has been capitalized by Clal Biotechnology Industries Ltd., the Pontifax Fund and Yissum Research Development Company Ltd., the technology transfer arm of the Hebrew University.

References

Weinstock M, Bejar C, Wang RH, et al. (2000). “TV3326, a novel neuroprotective drug with cholinesterase and monoamine oxidase inhibitory activities for the treatment of Alzheimer’s disease”. Journal of Neural Transmission. Supplementum (60): 157–69.PMID 11205137.
Weinreb O, Mandel S, Bar-Am O, et al. (January 2009). “Multifunctional neuroprotective derivatives of rasagiline as anti-Alzheimer’s disease drugs”. Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics 6 (1): 163–74.doi:10.1016/j.nurt.2008.10.030. PMID 19110207.
Weinstock M, Luques L, Bejar C, Shoham S (2006). “Ladostigil, a novel multifunctional drug for the treatment of dementia co-morbid with depression”. Journal of Neural Transmission. Supplementum (70): 443–6. PMID 17017566.
Weinreb O, Amit T, Bar-Am O, Youdim MB (December 2007). “Induction of neurotrophic factors GDNF and BDNF associated with the mechanism of neurorescue action of rasagiline and ladostigil: new insights and implications for therapy”. Annals of the New York Academy of Sciences 1122: 155–68.doi:10.1196/annals.1403.011. PMID 18077571.
Weinstock M, Poltyrev T, Bejar C, Youdim MB (March 2002). “Effect of TV3326, a novel monoamine-oxidase cholinesterase inhibitor, in rat models of anxiety and depression”.Psychopharmacology 160 (3): 318–24. doi:10.1007/s00213-001-0978-x. PMID 11889501.
Weinstock M, Gorodetsky E, Poltyrev T, Gross A, Sagi Y, Youdim M (June 2003). “A novel cholinesterase and brain-selective monoamine oxidase inhibitor for the treatment of dementia comorbid with depression and Parkinson’s disease”. Progress in Neuro-psychopharmacology & Biological Psychiatry 27 (4): 555–61. doi:10.1016/S0278-5846(03)00053-8.PMID 12787840.

Contact Us

Yona Geffen CEO
Avraham Pharmaceuticals Ltd.
42 Hayarkon st.
Northern Industrial Zone
Yavneh, 81227
Israel

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Ladostigil
Systematic (IUPAC) name

[(3R)-3-(prop-2-ynylamino)indan-5-yl]-N-propylcarbamate
Clinical data
Routes of administration	Oral
Legal status
Legal status	Uncontrolled
Identifiers
CAS Number	209349-27-4
ATC code	none
PubChem	CID 208907
ChemSpider	181005
UNII	SW3H1USR4Q
Synonyms	[N-propargyl-(3R)-aminoindan-5yl]-N-propylcarbamate
Chemical data
Formula	C₁₆H₂₀N₂O₂
Molar mass	272.34 g/mol

///////////Ladostigil, TV-3,326

c1c(cc2c(c1)CC[C@H]2NCC#C)OC(=O)N(CC)C

EDQM’s new Guideline on Electronic Submissions for CEP Applications

June 2, 2016 11:47 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

EDQM’s new Guideline on Electronic Submissions for CEP Applications

As of today (June, 1st 2016), the EDQM doesn’t accept any CEP application in paper format. Read more here about the structure of the electronic submission of an application for a Certificate of Suitability and the errors to avoid.

SEE

http://www.gmp-compliance.org/enews_05380_EDQM-s-new-Guideline-on-Electronic-Submissions-for-CEP-Applications_15429,15332,S-WKS_n.html

The EDQM has recently published a document entitled “Guidance for electronic submissions for Certificates of Suitability (CEP) applications” (PA/PH/CEP (09) 108, 3R) in which the authority describes the requirements to be considered for the submission of an application for a CEP. Let us give you the most important message straight away: the EDQM now only accepts CEP applications in the electronic format since June 1st 2016.

Only the following formats are authorised within an application procedure: PDF, NeeS (non-eCTD electronic submission), VNeeS (the respective application format for veterinary purposes) and eCTD. A change of format during an ongoing…

View original post 320 more words

Results of a Survey on ICH Q3D “Elemental Impurities”

June 2, 2016 11:46 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

For most companies manufacturing APIs and pharmaceutical products, the implementation of ICH Q3D has a serious impact – as shown in a survey recently carried out by the ECA. Read more about the issues encountered by many companies regarding the assessment and control of elemental impurities and the kind of support they wish.

SEE

http://www.gmp-compliance.org/enews_05395_Results-of-a-Survey-on-ICH-Q3D-%22Elemental-Impurities%22_15499,15332,S-AYL_n.html

One and a half years after the official entry into force of the ICH Q3D Guideline for “Elemental Impurities” and several supporting documents from the ICH (e.g. “Training Package: Modules 0-7“) a number of questions as regards implementation remain.

In a survey recently performed by the ECA, questions were posed about the issues relating to the fulfilling of the requirements laid down in ICH Q3D. The feedback from almost 80 participants from medium and large pharmaceutical companies and API manufacturers located in Germany and other EU Member States shows remarkable results which harsh…

View original post 247 more words

Дапипразол Dapiprazole

June 1, 2016 10:39 am / Leave a comment

Dapiprazole

CAS 72822-12-9

HCL SALT 72822-13-0

5,6,7,8-Tetrahydro-3-(2-(4-(O-tolyl)-1-piperazinyl)ethyl)-S-triazolo(4,3-a)pyridine

Dapiprazole (Rev-Eyes) is an alpha blocker. It is used to reverse mydriasis after eye examination.^[1]

Used in the treatment of iatrogenically induced mydriasis produced by adrenergic (phenylephrine) or parasympatholytic (tropicamide) agents used in certain eye examinations.

Dapiprazole is an alpha-adrenergic blocking agent. It produces miosis by blocking the alpha-adrenergic receptors on the dilator muscle of the iris. Dapiprazole produces no significant action on ciliary muscle contraction and thus, there are no changes in the depth of the anterior chamber of the thickness of the lens. It does not alter the IOP either in normal eyes or in eyes with elevated IOP. The rate of pupillary constriction may be slightly slower in clients with brown irises than in clients with blue or green irises.

Dapiprazole acts through blocking the alpha1-adrenergic receptors in smooth muscle. It produces miosis through an effect on the dilator muscle of the iris and does not have any significant activity on ciliary muscle contraction and, therefore does not induce a significant change in the anterior chamber depth or the thickness of the lens.

Oral LD₅₀ is 1189-2100 mg/kg in mice, rats and rabbits.

Brief background information

Salt	ATC	formula	MM	CASE
–	N05AX S01EX02	C₁₉H₂₇N₅	325.46 g / mol	72822-12-9
monogïdroxlorïd	N05AX S01EX02	C₁₉H₂₇N₅ · HCl	361.92 g / mol	72822-13-0

Application

antipsihoticheskoe means
in the treatment of glaucoma

Classes substance

Piperazinы
- 1,2,4-triazolo [4,3-a] piridinы

Synthesis

Синтез a)


Scheme illustration:By cyclization of O-methylvalerolactam (I) with 3-(4-o-tolyl-1-piperazinyl) propionic acid hydrazide (II) in refluxing xylene, followed by a treatment with ethanolic HCl.

FR 2423221; GB 2020269; JP 54157576; NL 7902489; US 4252721

Acylation of (1-methylcyclopropyl)guanidine (IV) with 3-bromo-5-chlorothiophene-2-sulfonyl chloride (III) under Schotten-Baumann conditions afforded the sulfonyl guanidine (V). This was cyclized to the desired thienothiadiazine upon treatment with Cs2CO3 and Cu2O in boiling butanol.

In a different method, (1-methylcyclopropyl)guanidine (I) is acylated by 3-bromo-5-chlorothiophene-2-sulfonyl chloride (II) to produce the sulfonyl guanidine (III). Intramolecular cyclization of (III) in the presence of Cu2O and Cs2CO3 leads to the title thienothiadiazine derivative. Similarly, acylation of guanidine (I) with 3,5-dichlorothiophene-2-sulfonyl chloride (IV) provides sulfonyl guanidine (V), which is then cyclized in the presence of Cu2O and Cs2CO3.

In an alternative method, sulfonylation of N-isopropylguanidine (V) with 2,5-dichlorothiophene-3-sulfonyl chloride (IV) produced the sulfonyl guanidine (VI). This was then cyclized to the title compound by treatment with copper bronze and potassium carbonate in boiling DMF……..WO 0102410

Trade names

country	Tradename	Manufacturer
Germany	Remidrial	winegrower
Italy	Glamidolo	Angelini, 1987
Ukraine	no	no

Formulations

eyedrops 50 mg / 10 ml (5%) (hydrochloride)

References

DE 2 915 318 (Angelini; appl. 14.4.1979; I-prior. 18.4.1978).
US 4 307 095 (Angelini; 22.12.1981; prior. 29.3.1979, 29.8.1980; I-prior. 18.4.1978).
US 4 307 096 (Angelini; 22.12.1981; prior. 29.3.1979, 29.8.1980; I-prior. 18.4.1978).
US 4 325 952 (Angelini; 20.4.1982; prior. 29.3.1979, 29.8.1980; I-prior. 18.4.1978).
BE 877 161 (Angelini; appl. 21.6.1979).

References

Doughty, Michael J.; Lyle, William M. (May 1992). “A Review of the Clinical Pharmacokinetics of Pilocarpine, Moxisylyte (Thymoxamine), and Dapiprazole in the Reversal of Diagnostic Pupillary Dilation”. Optometry & Vision Science 69 (5).
US 4 307 096 (Angelini; 22.12.1981; prior. 29.3.1979, 29.8.1980; I-prior. 18.4.1978).
US 4 325 952 (Angelini; 20.4.1982; prior. 29.3.1979, 29.8.1980; I-prior. 18.4.1978).
BE 877 161 (Angelini; appl. 21.6.1979).
DE 2 915 318 (Angelini; appl. 14.4.1979; I-prior. 18.4.1978).
US 4 307 095 (Angelini; 22.12.1981; prior. 29.3.1979, 29.8.1980; I-prior. 18.4.1978).

Structural formula

UV- Spectrum

The solvent designation schedule	methanol	water	0.1М HCl	0.1M NaOH

Conditions : Concentration – 1 mg / 100 ml
maximum absorption	235 nm	235 nm	234 nm	There decay
	212	179	172	–
e	7650	6450	6200	–

IR – spectrum

Wavelength (μm)

Wave number (cm ^-1 )

References

UV and IR Spectra. H.-W. Dibbern, R.M. Muller, E. Wirbitzki, 2002 ECV
NIST/EPA/NIH Mass Spectral Library 2008
Handbook of Organic Compounds. NIR, IR, Raman, and UV-Vis Spectra Featuring Polymers and Surfactants, Jr., Jerry Workman. Academic Press, 2000.
Handbook of ultraviolet and visible absorption spectra of organic compounds, K. Hirayama. Plenum Press Data Division, 1967.

Dapiprazole
Systematic (IUPAC) name

3-{2-[4-(2-methylphenyl)piperazin-1-yl]ethyl}-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,5-a]pyridine
Clinical data
AHFS/Drugs.com	Consumer Drug Information
MedlinePlus	a601043
Pregnancy category	B
Routes of administration	Topical (eye drops)
Legal status
Legal status	℞ (Prescription only)
Pharmacokinetic data
Bioavailability	Negligible when administered topically
Identifiers
CAS Number	72822-12-9
ATC code	S01EX02 (WHO)
PubChem	CID 3033538
IUPHAR/BPS	7155
DrugBank	DB00298
ChemSpider	2298190
UNII	5RNZ8GJO7K
KEGG	D07775
ChEBI	CHEBI:51066
ChEMBL	CHEMBL1201216
Chemical data
Formula	C₁₉H₂₇N₅
Molar mass	325.451 g/mol

//////Дапипразол , Dapiprazole, AF-2139, Remydrial, Rev-Eyes, Reversil, Glamidolo

n1nc(n2c1CCCC2)CCN4CCN(c3ccccc3C)CC4

[F-18](2S,4S)-4-(3-Fluoropropyl)glutamine

May 30, 2016 11:05 am / Leave a comment

[F-18](2S,4S)-4-(3-Fluoropropyl)glutamine

CAS 1196963-79-7

MF C₈ H₁₅ F N₂ O₃

Heptanoic acid, 2-amino-4-(aminocarbonyl)-7-(fluoro-¹⁸F)-, (2S,4S)-


[¹⁸F](2S,4S)-4-FPGln	[¹⁸F](2S,4S)-4-(3-fluoropropyl)glutamine, 4

The early diagnosis of malignant tumors plays a very important role in the survival prognosis of cancer patients. In this non-invasive diagnosis, diagnostic imaging procedures are an important tool. In the last few years has mainly PET technology (P ositronen- E mission- Tomographie) proved to be particularly useful. The sensitivity and specificity of PET technology depends significantly on the used signal-emitting substance (tracer) and their distribution in the body from. In the search for suitable tracers one tries to take advantage of certain properties of tumors differ, the tumor tissue from healthy, surrounding tissue. The preferred commercially used isotope which finds application for PET, ¹⁸ F ¹⁸ F represents by its short half-life of less than 2 hours special requirements for the preparation of suitable tracer. Complex, long synthetic routes and purifications are with this isotope is not possible, because otherwise a significant portion of the radioactivity of the isotope has already decayed before the tracer can be used for diagnosis. It is therefore often not possible to established synthetic routes for non-radioactive fluorination to be applied to the synthesis of¹⁸ F-tracer. Furthermore, the high specific activity of ¹⁸ F (80 GBq / nmol) at very low substance amounts of ^[18 F] fluoride for the tracer synthesis, which in turn an extreme excess of precursor-related and the success of a non-radioactive fluorination based Radio synthetic strategy designed unpredictable

FDG ^([18 F] F 2 luoro d esoxy lukose g) -PET is a widely accepted and popular tool in the diagnosis and other clinical tracking of tumor diseases. Malignant tumors compete with the host organism to glucose supply to the nutrient supply (Warburg O. About the metabolism of carcinoma cell Biochem;.. Kellof G. Progress and Promise of FDG PET Imaging for Cancer Patient Management and Oncologic Drug Development Clin Cancer Res 2005;.. 11 (8): 2785-2807) where tumor cells compared to surrounding cells of normal tissue usually an increased glucose metabolism. This is used when using fluorodeoxyglucose (FDG), a glucose derivative, which is amplified transported into the cells, but there included metabolically after phosphorylation as FDG-6-phosphate (“Warburg effect”). ¹⁸ F-labeled FDG is Therefore, an effective tracer for the detection of tumors in patients using PET technology. Imaging were looking for new PET tracers in recent years increasingly amino acids for ¹⁸ F PET used (eg (review): Eur J Nucl Med Mol Imaging 2002 May; 29 (5):.. 681-90). In this case, some of the ¹⁸ F-labeled amino acids for the measurement of the speed rate of protein synthesis, the most useful derivatives but for the direct measurement of the cellular uptake in the tumor. Known ¹⁸ F-labeled amino acids are, for example, from tyrosine, phenylalanine, proline, aspartic and unnatural amino acids derived (eg J. Nucl Med 1991; 32:.. 1338-1346, J Nucl Med 1996; 37: 320-325, J Nucl Med 2001; 42: 752-754 J Nucl Med and 1999, 40: 331-338).. Glutamic acid and glutamine than ¹⁸ F-labeled derivatives not known, whereas non-radioactive fluorinated glutamine and glutamic acid derivatives are well known; Thus, for Example those which at γ-position (for Ex (review):Amino Acids (2003) April; 24 (3):… 245-61).. or at β-position (e.g. ExTetrahedron. Lett. .; 30; 14; 1989, 1799-1802, J. Org Chem .; 54; 2; 1989, 498-500, Tetrahedron: Asymmetry, 12, 9; 2001; 1303-1312) havefluorine..

Of glutamic acid having the chemical functionalities protecting groups in β and γ position or a leaving group, has already been reported in the past. So was informed of glutamate as mesylate or bromide in γ-position whose acid and amine functions were provided with ester or Z-protecting groups (J. Chem Soc Perkin Trans. 1;.. 1986, 1323-1328) or, for example, of γ-chloro-glutamic acid without protecting groups(Synthesis, (1973); 44-46). About similar derivatives, but where the leaving group is positioned in β-position has also been reported on several occasions. Z Ex. Chem. Pharm. Bull .; 17; 5; (1969); 879-885,J.Gen.Chem.USSR (Engl.Transl.); 38; (1968); 1645-1648, Tetrahedron Lett .; 27; 19; (1986); 2143-2144, Chem. Pharm. Bull .; EN; 17; 5; 1969;873-878, patent FR 1461184 , Patent JP 13142 .)

The current PET tracers, which are used for tumor diagnosis have some undisputed disadvantages: in FDG accumulates preferably in those cells with increased glucose metabolism on, but there are also other pathological and physiological conditions of increased glucose metabolism in the cells involved and tissues, eg, Ex. of infection or wound healing (summarized in J. Nucl. Med. Technol. (2005), 33, 145-155). It is still often difficult to decide whether a detected by FDG-PET lesion actually neoplastic origin or due to other physiological or pathological state of the tissue. Overall, the diagnostic activity by FDG-PET in oncology has a sensitivity of 84% and a specificity of 88% to(Gambhir et al., ” A tabulated summary of the FDG PET literature “J. Nucl. Med. 2001, 42, 1- 93S). Tumors in the brain can be represented very difficult in healthy brain tissue, for example, by the high accumulation of FDG.

The previously known ¹⁸ F-labeled amino acid derivatives are in some cases well suited to detect tumors in the brain ((review): Eur J Nucl Med Mol Imaging 2002 May; 29 (5):. 681-90), but they can in other tumors do not compete with the imaging properties of the “gold standard” ^[18 F] 2-FDG. The metabolic accumulation and retention of previously F-18 labeled amino acids in tumorous tissue is usually lower than for FDG. Moreover, the accessibility of isomerically pure F-18-labeled non-aromatic amino acids is chemically very demanding.

Similar to glucose increased metabolism in proliferating tumor cells has been described (Medina, J Nutr 1131: 2539S-2542S, 2001; Souba, Ann Surg 218:. 715-728, 1993) for glutamic acid and glutamine. The increased rate of protein and nucleic acid synthesis and energy production per se be accepted as reasons for increased Glutaminkonsum of tumor cells. The synthesis of the corresponding C-11 and C-14 labeled with the natural substrate thus identical compounds, has already been described in the literature (eg. Ex.Antoni, enzymes Catalyzed Synthesis of L- [4-C-11] Aspartate and L – [5-C-11] Glutamate J. Labelled Compd Radiopharm 44; (4) 2001: 287-294) and Buchanan, The biosynthesis of showdomycin: studies with stable isotopes and the determination of principal precursor J….. Chem. Soc. Chem. Commun .; EN; 22; 1984, 1515-1517). First indications with the C-11 labeled compound indicate no significant tumor accumulation.

Although the growth and proliferation of most tumors is fueled by glucose, some tumors are more likely to metabolize glutamine. In particular, tumor cells with the upregulated c-Myc gene are generally reprogrammed to utilize glutamine. We have developed new 3-fluoropropyl analogs of glutamine, namely [(18)F](2S,4R)- and [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 3 and 4, to be used as probes for studying glutamine metabolism in these tumor cells. Optically pure isomers labeled with (18)F and (19)F (2S,4S) and (2S,4R)-4-(3-fluoropropyl)glutamine were synthesized via different routes and isolated in high radiochemical purity (≥95%). Cell uptake studies of both isomers showed that they were taken up efficiently by 9L tumor cells with a steady increase over a time frame of 120 min. At 120 min, their uptake was approximately two times higher than that of l-[(3)H]glutamine ([(3)H]Gln). These in vitro cell uptake studies suggested that the new probes are potential tumor imaging agents. Yet, the lower chemical yield of the precursor for 3, as well as the low radiochemical yield for 3, limits the availability of [(18)F](2S,4R)-4-(3-fluoropropyl)glutamine, 3. We, therefore, focused on [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 4. The in vitro cell uptake studies suggested that the new probe, [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, is most sensitive to the LAT transport system, followed by System N and ASC transporters. A dual-isotope experiment using l-[(3)H]glutamine and the new probe showed that the uptake of [(3)H]Gln into 9L cells was highly associated with macromolecules (>90%), whereas the [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, was not (<10%). This suggests a different mechanism of retention. In vivo PET imaging studies demonstrated tumor-specific uptake in rats bearing 9L xenographs with an excellent tumor to muscle ratio (maximum of ∼8 at 40 min). [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, may be useful for testing tumors that may metabolize glutamine related amino acids.

[¹⁸F](2S,4S)-4-(3-Fluoropropyl)glutamine as a Tumor Imaging Agent

http://pubs.acs.org/doi/full/10.1021/mp500236y

Zehui Wu†, Zhihao Zha†, Genxun Li†, Brian P. Lieberman†, Seok Rye Choi†, Karl Ploessl†, and Hank F. Kung^*†‡

^†Departments of Radiology and ^‡Pharmacology, University of Pennsylvania, 3700 Market Street, Philadelphia, Pennsylvania 19104, United States

Mol. Pharmaceutics, 2014, 11 (11), pp 3852–3866

DOI: 10.1021/mp500236y

Publication Date (Web): August 05, 2014

*Email: kunghf@sunmac.spect.upenn.edu. Phone: 215-662-3096. Fax: 215-349-5035.

ACS AuthorChoice – 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.

This article is part of the Positron Emission Tomography: State of the Art special issue.

Abstract

Although the growth and proliferation of most tumors is fueled by glucose, some tumors are more likely to metabolize glutamine. In particular, tumor cells with the upregulated c-Myc gene are generally reprogrammed to utilize glutamine. We have developed new 3-fluoropropyl analogs of glutamine, namely [¹⁸F](2S,4R)- and [¹⁸F](2S,4S)-4-(3-fluoropropyl)glutamine, 3 and 4, to be used as probes for studying glutamine metabolism in these tumor cells. Optically pure isomers labeled with ¹⁸F and ¹⁹F (2S,4S) and (2S,4R)-4-(3-fluoropropyl)glutamine were synthesized via different routes and isolated in high radiochemical purity (≥95%). Cell uptake studies of both isomers showed that they were taken up efficiently by 9L tumor cells with a steady increase over a time frame of 120 min. At 120 min, their uptake was approximately two times higher than that of l-[³H]glutamine ([³H]Gln). These in vitro cell uptake studies suggested that the new probes are potential tumor imaging agents. Yet, the lower chemical yield of the precursor for 3, as well as the low radiochemical yield for 3, limits the availability of [¹⁸F](2S,4R)-4-(3-fluoropropyl)glutamine, 3. We, therefore, focused on [¹⁸F](2S,4S)-4-(3-fluoropropyl)glutamine, 4. The in vitro cell uptake studies suggested that the new probe, [¹⁸F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, is most sensitive to the LAT transport system, followed by System N and ASC transporters. A dual-isotope experiment using l-[³H]glutamine and the new probe showed that the uptake of [³H]Gln into 9L cells was highly associated with macromolecules (>90%), whereas the [¹⁸F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, was not (<10%). This suggests a different mechanism of retention. In vivo PET imaging studies demonstrated tumor-specific uptake in rats bearing 9L xenographs with an excellent tumor to muscle ratio (maximum of ∼8 at 40 min). [¹⁸F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, may be useful for testing tumors that may metabolize glutamine related amino acids.

PATENT

US 20100290991

http://www.google.com/patents/US20100290991

PATENT

WO 2009141091

https://patentscope.wipo.int/search/ko/detail.jsf?docId=WO2009141091&recNum=70&maxRec=287&office=&prevFilter=%26fq%3DOF%3ACU&sortOption=Relevance&queryString=&tab=PCTDescription

PATENT

http://www.google.co.ug/patents/EP2123621A1?cl=en

REFERENCES

https://www.researchgate.net/publication/264538736_F-182S4S-4-3-Fluoropropylglutamine_as_a_Tumor_Imaging_Agent

Molecular Pharmaceutics (2014), 11(11), 3852-3866

EP1923382A1 *	18 Nov 2006	21 May 2008	Bayer Schering Pharma Aktiengesellschaft	[18F] labelled L-glutamic acid, [18F] labelled glutamine, their derivatives, their use and processes for their preparation
FR1461184A				Title not available
JPS58113142A				Title not available
WO2008052788A1 *	30 Oct 2007	8 May 2008	Bayer Schering Pharma Aktiengesellschaft	[f-18]-labeled l-glutamic acid, [f-18]-labeled l-glutamine, derivatives thereof and use thereof and processes for their preparation

////////

[18F]AMG 580

May 30, 2016 11:01 am / Leave a comment

[¹⁸F]AMG 580

CAS 1879904-74-1

MF C₂₆ H₂₄ F N₅ O₃

NOTE………CAS OF AMG 580 IS 1227067-71-1, WITHOUT 18F

AMG 580 [1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one],

Phosphodiesterase 10A (PDE10A) inhibitors have therapeutic potential for the treatment of psychiatric and neurologic disorders, such as schizophrenia and Huntington’s disease. One of the key requirements for successful central nervous system drug development is to demonstrate target coverage of therapeutic candidates in brain for lead optimization in the drug discovery phase and for assisting dose selection in clinical development. Therefore, we identified AMG 580 [1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one], a novel, selective small-molecule antagonist with subnanomolar affinity for rat, primate, and human PDE10A. We showed that AMG 580 is suitable as a tracer for lead optimization to determine target coverage by novel PDE10A inhibitors using triple-stage quadrupole liquid chromatography–tandem mass spectrometry technology. [³H]AMG 580 bound with high affinity in a specific and saturable manner to both striatal homogenates and brain slices from rats, baboons, and human in vitro. Moreover, [¹⁸F]AMG 580 demonstrated prominent uptake by positron emission tomography in rats, suggesting that radiolabeled AMG 580 may be suitable for further development as a noninvasive radiotracer for target coverage measurements in clinical studies. These results indicate that AMG 580 is a potential imaging biomarker for mapping PDE10A distribution and ensuring target coverage by therapeutic PDE10A inhibitors in clinical studies.

PAPER

We report the discovery of PDE10A PET tracer AMG 580 developed to support proof of concept studies with PDE10A inhibitors in the clinic. To find a tracer with higher binding potential (BP_ND) in NHP than our previously reported tracer 1, we implemented a surface plasmon resonance assay to measure the binding off-rate to identify candidates with slower washout rate in vivo. Five candidates (2–6) from two structurally distinct scaffolds were identified that possessed both the in vitro characteristics that would favor central penetration and the structural features necessary for PET isotope radiolabeling. Two cinnolines (2, 3) and one keto-benzimidazole (5) exhibited PDE10A target specificity and brain uptake comparable to or better than 1 in the in vivo LC–MS/MS kinetics distribution study in SD rats. In NHP PET imaging study, [¹⁸F]-5 produced a significantly improved BP_ND of 3.1 and was nominated as PDE10A PET tracer clinical candidate for further studies.

Discovery of Phosphodiesterase 10A (PDE10A) PET Tracer AMG 580 to Support Clinical Studies

^†Department of Medicinal Chemistry, ^‡Department of Pharmacokinetics and Drug Metabolism, ^§Department of Neuroscience, and ^ΔDepartment of Early Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 93012-1799, United States

^∥Department of Neuroscience and ^±Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States

^⊥ Department of Molecular Structure and Characterization, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States

ACS Med. Chem. Lett., Article ASAP

DOI: 10.1021/acsmedchemlett.6b00185

*Phone: 805-313-5300. E-mail: ehu@amgen.com.

SEE http://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.6b00185

PATENT FOR AMG 580

WO 2010057121

https://www.google.com/patents/WO2010057121A1?cl=en

PAPER

Nuclear Medicine and Biology (2015), 42(8), 654-663.

http://www.sciencedirect.com/science/article/pii/S0969805115000724

Phosphodiesterase 10A (PDE10A) is an intracellular enzyme responsible for the breakdown of cyclic nucleotides which are important second messengers for neurotransmission. Inhibition of PDE10A has been identified as a potential target for treatment of various neuropsychiatric disorders. To assist drug development, we have identified a selective PDE10A positron emission tomography (PET) tracer, AMG 580. We describe here the radiosynthesis of [¹⁸ F]AMG 580 and in vitro and in vivo characterization results.

AMG 580 has an in vitro K_D of 71.9 pM. Autoradiography showed specific uptake in striatum. Mean activity of 121 ± 18 MBq was used in PET studies. In Rhesus, the baseline BP_ND for putamen and caudate was 3.38 and 2.34, respectively, via 2TC, and 3.16, 2.34 via Logan, and 2.92, and 2.01 via SRTM. A dose dependent decrease of BP_NDwas observed by the pre-treatment with a PDE10A inhibitor. In baboons, 0.24 mg/kg dose of AMG 580 resulted in about 70% decrease of BP_ND. The in vivo K_D of [¹⁸ F]AMG 580 was estimated to be around 0.44 nM in baboons.

Conclusion

[¹⁸ F]AMG 580 is a selective and potent PDE10A PET tracer with excellent specific striatal binding in non-human primates. It warrants further evaluation in humans.

REFERNCES

http://jpet.aspetjournals.org/content/352/2/327.full

///Phosphodiesterase, tracer, receptor occupancy, positron emission tomography, radiotracer, brain penetration, AMG 580, Phosphodiesterase 10A, PDE10A, PET Tracer, [¹⁸F]AMG 580

WHO issues revised Guideline on HVAC Systems

May 26, 2016 9:48 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

The World Health Organization (WHO) recently issued a guideline for commenting which describes the requirements for HVAC systems for the manufacture of non-sterile forms. As most guidelines on this topic address the requirements for sterile dosage forms, the previous version was gladly accepted by industry. Learn more about the revised guideline on HVAC systems.

http://www.gmp-compliance.org/enews_05358_WHO-issues-revised-Guideline-on-HVAC-Systems_15160,15221,15661,15612,Z-PEM_n.html

The World Health Organization (WHO) recently issued a guideline for commenting which describes the requirements for HVAC systems used for the manufacture of non-sterile dosage forms. As most guidelines on this topic address the requirements for sterile forms, the previous version (TRS 961, Annex 1) from 2011 was gladly accepted by industry. Mentioned are non-sterile dosage forms as tablets, capsules, liquids or ointments, but also for the final steps in the manufacture of APIs. The WHO guideline means to provide guidance specifically for the areas design, installation, qualification and maintenance of ventilation systems. For the manufacture of…

View original post 192 more words

EU GMP Annex 1 Revision 2016 – what does the pharmaceutical industry expect?

May 26, 2016 9:45 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

Dr Friedrich Haefele, Vice President Fill & Finish Biopharma at Boehringer Ingelheim

Dr Friedrich Haefele, Vice President Fill & Finish Biopharma at Boehringer Ingelheim talked in his keynote speech at the Pharma Congress 2016 about the revision of Annex 1 of the EU GMP Guide. Read here what the pharmaceutical industry expects form the new Annex 1.

http://www.gmp-compliance.org/enews_05326_EU-GMP-Annex-1-Revision-2016—what-does-the-pharmaceutical-industry-expect_15160,15266,15265,15432,Z-PEM_n.html

Europe’s biggest Pharma Congress of its kind took place in Düsseldorf on 12 and 13 April. With more than 1000 participants, 90 exhibitors and 10 GMP conferences this Congress 2016 has been the biggest since the first one 18 years ago. 50 lectures, almost exclusively case studies from pharmacuetical companies such as Pfizer, Novartis, Boehringer Ingelheim and many more were discussed. Special attention was paid to the keynotes at the beginning of each congress day.

Dr Friedrich Haefele, Vice President Fill & Finish Biopharma at Boehringer Ingelheim talked in his keynote…

View original post 876 more words

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Novel Series of Potent Glucokinase Activators Leading to the Discovery of AM-2394

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COPYING ERROR

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Primary biliary cirrhosis

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Portal hypertension

Bile acid diarrhea

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Yaacov Michlin appointed Chairman of the Board and Dr. Yona Geffen appointed Chief Executive Officer

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FR 2423221; GB 2020269; JP 54157576; NL 7902489; US 4252721

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[F-18](2S,4S)-4-(3-Fluoropropyl)glutamine

[18F](2S,4S)-4-(3-Fluoropropyl)glutamine as a Tumor Imaging Agent

Abstract

[18F]AMG 580

PAPER

Discovery of Phosphodiesterase 10A (PDE10A) PET Tracer AMG 580 to Support Clinical Studies

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[¹⁸F](2S,4S)-4-(3-Fluoropropyl)glutamine as a Tumor Imaging Agent

[¹⁸F]AMG 580