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ACT-132577, Aprocitentan

May 19, 2024 9:08 am / Leave a comment

ACT-132577, Aprocitentan,

N-Despropyl-macitentan

1103522-45-7

546.19, C₁₆H₁₄Br₂N₆O₄S

WHO 10552

3/19/2024 FDA APPROVED, To treat hypertension, Tryvio

N-[5-(4-bromophenyl)-6-{2-[(5-bromopyrimidin-2-yl)oxy]ethoxy}pyrimidin-4-yl]aminosulfonamide

Aprocitentan, sold under the brand name Tryvio, is a medication used to treat hypertension (high blood pressure).^[1] It is developed by Idorsia.^[2] It is taken by mouth.^[1]

Aprocitentan is a dual endothelin-1 antagonist that targets both endothelin A and endothelin B receptors.^[3]^[4]

Aprocitentan was approved for medical use in the United States in March 2024.^[1]^[2]^[5] It is the first endothelin receptor antagonist to be approved by the US Food and Drug Administration (FDA) to treat systemic hypertension.^[2]

Medical uses

Aprocitentan is indicated for the treatment of hypertension in combination with other antihypertensive drugs, to lower blood pressure in adults who are not adequately controlled on other medications.^[1]

Adverse effects

Aprocitentan may cause hepatotoxicity (liver damage), edema (fluid retention), anemia (reduced hemoglobin), and decreased sperm count.^[1]

Contraindications

Data from animal reproductive toxicity studies with other endothelin-receptor agonists indicate that use is contraindicated in pregnant women.^[1]

Mechanism of action

Aprocitentan is an endothelin receptor agonist that inhibits the protein endothelin-1 from binding to endothelin A and endothelin B receptors.^[1]^[4] Endothelin-1 mediates various adverse effects via its receptors, such as inflammation, cell proliferation, fibrosis, and vasoconstriction.^[1]

Society and culture

Economics

Aprocitentan is developed by Idorsia, which sold it to Janssen and purchased the rights back in 2023, for US$343 million.^[6]

Legal status

Aprocitentan was approved for medical use in the United States in March 2024.^[1]

In April 2024, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Jeraygo, intended for the treatment of resistant hypertension in adults.^[7] The applicant for this medicinal product is Idorsia Pharmaceuticals Deutschland GmbH.^[7]

SYN

US Patent

Trade Name

Application Number

Applicant

8324232

TRYVIO

217686

IDORSIA PHARMACEUTICALS LTD

11174247

TRYVIO

217686

IDORSIA PHARMACEUTICALS LTD

11787782

TRYVIO

217686

IDORSIA PHARMACEUTICALS LTD

11680058

TRYVIO

217686

IDORSIA PHARMACEUTICALS LTD

10919881

TRYVIO

217686

IDORSIA PHARMACEUTICALS LTD

PATENT

WO 02/053557

PATENT

Martin Bolli, Christoph Boss, Alexander Treiber. ” 4-pyrimidinesulfamide derivative “, US Patent US8324232B2.

https://patentscope.wipo.int/search/en/detail.jsf?docId=US73589939&_cid=P12-LWDB8Y-85368-1

EXAMPLE

The following example was prepared according to the procedures described below. All compounds were characterized by ¹H-NMR (300 MHz) and occasionally by ¹³C-NMR (75 MHz) (Varian Oxford, 300 MHz; chemical shifts are given in ppm relative to the solvent used; multiplicities: s=singlet, d=doublet, t=triplet; m=multiplet), by LC-MS (Finnigan Navigator with HP 1100 Binary Pump and DAD, column: 4.6×50 mm, Develosil RP Aqueous, 5 μm, 120 A, gradient: 5-95% acetonitrile in water, 1 min, with 0.04% trifluoroacetic acid, flow: 4.5 ml/min), t _Ris given in min; by TLC (TLC-plates from Merck, Silica gel 60 F ₂₅₄) and occasionally by melting point.

Preparation A: Benzylsulfamide Potassium Salt

A.i. Benzylsulfamide

Chlorosulfonylisocyanate (14.14 g) was dissolved in DCM (50 mL) and cooled to 0° C. A solution of t-BuOH (9.6 mL) in DCM (50 mL) was added within 30 min. Stirring was continued for additional 30 min at rt. The solution thus obtained was then added at 0° C. within 1 h to a solution of benzylamine (10.7 g) and TEA (15.32 mL) in DCM (200 mL). Stirring is continued for 10 h at rt. The mixture was concentrated in vacuo, taken up in EA (500 mL) and washed with water (2×40 mL) and brine (30 mL), dried over MgSO ₄, filtered. The filtrate was concentrated in vacuo and the crude material was crystallized from EA and dried under HV to give N-benzyl-N′-tert-butoxycarbonyl sulfamide (13.68 g).

¹H NMR (CDCl ₃): δ 1.46 (s, 9H); 4.25 (s, 2H); 5.42 (s br., 1H); 7.30-7.40 (m, 5H).

LC-MS: t _R=0.90 min, [M+H] ⁺=287.09.

This material was dissolved in dioxane (20 ml) and 4 M HCl in dioxane (120 mL) was added within 1 h at rt. The mixture was stirred for 8 h before the solvent was evaporated and the residue dried under HV to give benzylsulfamide as an off-white powder (9.47 g).

¹H NMR (D ₆-DMSO): δ 4.05 (d, J=6.4 Hz, 2H); 6.60 (s, 2H); 7.04 (s, J=6.4 Hz, 1H); 7.20-7.36 (m, 5H).

LC-MS: t _R=0.60 min, [M+H+CH ₃CN] ⁺=228.17.

A.ii. Benzylsulfamide Potassium Salt

To a solution of benzylsulfamide (17.98 g) in McOH (300 mL) was carefully added potassium tert-butylate (10.8 g). The mixture was stirred at rt for 15 min before the solvent was evaporated. The remaining residue was dried under HV to give benzylsulfamide potassium salt as an off-white powder (21.73 g).

Preparation B: 5-(4-bromo-phenyl)-4,6-dichloro-pyrimidine

B.i. 4-bromophenylacetic acid methyl ester

To a solution of 4-bromophenylacetic acid (50 g) in methanol (250 ml) was added dropwise thionyl chloride (34.2 mL) while the temperature of the reaction mixture was kept at 0-5° C. Upon complete addition cooling was stopped and the mixture was allowed to warm to rt. Stirring was continued for 75 min before the solvent was removed in vacuo. The yellow oil was dissolved in benzene and again concentrated. The residue was dissolved in EA, washed with water, brine, 2 N aq. Na ₂CO ₃, and again brine. The org. extract was dried over MgSO ₄, filtered, concentrated and dried under HV at 85° C. for 30 min to give the expected product as a yellow oil (52.4 g).

¹H-NMR (D ₆-DMSO): δ 3.60 (s, 3H); 3.67 (s, 2H); 7.22 (d, 8.5, 2H); 7.50 (d, J=8.5 Hz, 2H).

B.ii. 2-(4-bromophenyl)-malonic acid dimethyl ester

At 40° C., a solution of intermediate B.i (52 g) in THF (100 mL) was carefully added over a period of 40 min to a suspension of NaH (15.6 g) in dry THF (450 mL). Stirring was continued for 70 min without heating and the temperature dropped to 27° C. The evolution of gas stopped before dimethylcarbonate (76.42 mL) was added dropwise while the temperature of the mixture was maintained at 29-31° C. Stirring was continued for 22 h at rt. The mixture was cooled to −10° C. and then carefully neutralized to pH 6-7 with aq. HCl before bulk of the THF was removed in vacuo. The residue was dissolved in EA (700 mL), washed 3 times with 1 N aq. HCl-solution and once with brine, dried over MgSO ₄. Most of the EA was evaporated before Hex was added. The product crystallised overnight at 4° C. The crystals were collected, washed with Hex and dried to give the expected product as pale yellow crystals (45.9 g).

¹H-NMR (D ₆-DMSO): δ 3.66 (s, 6H); 5.07 (s, 1H); 7.30-7.34 (m, 2H); 7.55-7.59 (m, 2H),

B.iii. 5-(4-bromophenyl)-pyrimidine-4,6-diol

A solution of intermediate B.ii (11.73 g) in MeOH (100 mL) was added at 0° C. to a solution of sodium (2.83 g) in MeOH (100 mL). The mixture was stirred for 18 h at rt before formamidine hydrochloride (4.10 g) was added. The suspension was stirred at rt for 4 h. The solvent was removed and the residue was suspended in 10% aq. citric acid (100 mL) and stirred for 10 min. The white precipitate was collected, washed with 10% aq. citric acid, water, evaporated three times from cyclohexane and dried under HV at 40° C. to give 5-(4-bromophenyl)-pyrimidine-4,6-diol as a pale beige powder (9.90 g).

¹H-NMR (D ₆-DMSO): δ 7.43-7.48 (m, 2H), 7.50-7.55 (m, 2H), 8.13 (s, 1H), 12.1 (s br., 2H).

LC-MS: t _R=0.62 min, [M+H] ⁺=266.89/268.89 (Br-isotopes).

B.iv. 5-(4-bromo-phenyl)-4,6-dichloro-pyrimidine

To a suspension of 5-(4-bromophenyl)-pyrimidine-4,6-diol (9.90 g) in POCl ₃(130 mL) was carefully added N,N-dimethylaniline (13.5 mL). The mixture is heated to 130° C. for 2 h. The dark brown solution is concentrated in vacuo and the residue was poured into ice/water. The suspension is diluted with 2 N HCl and water and stirred for 20 min. The precipitate that formed is collected and washed with water. The solid material is dissolved in EA, washed with 1 N aq. HCl and brine. The org. phase is dried over MgSO ₄and evaporated. The material is further purified by column chromatography on silica gel eluting with Hex:EA 95:5 to 1:1 followed by crystallisation from Hex/EA at −20° C. to give 4,6-dichloro-5-(4-bromophenyl)-pyrimidine as pale yellow crystals (8.3 g).

¹H-NMR (D ₆-DMSO): δ 7.39-7.44 (m, 2H), 7.72-7.76 (m, 2H), 8.94 (s, 1H).

LC-MS: t _R=1.02 min.

Example 1

{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide

1.i. Benzyl-sulfamic acid [6-chloro-5-(4-bromophenyl)-pyrimidin-4-yl]-amide

A solution of 5-(4-bromophenyl)-4,6-dichloro-pyrimidine (4.00 g, 13.2 mmol) and benzylsulfamide potassium salt (7.38 g, 32.9 mmol) in DMSO (30 mL) was stirred at it for 24 h before being diluted with a 10% aq. citric acid solution (200 mL). The suspension that formed was filtered. The collected solid was washed well with water and dried under HV at 40° C. for 48 h to give the expected product as a white powder (6.15 g).

¹H NMR (CDCl ₃): δ 4.23 (d, J=5.9 Hz, 2H); 5.94 (t br., J=6 Hz, 1H); 7.05 (d, J=8.2 Hz, 2H); 7.20-7.35 (m, 5H); 7.68 (d, J=8.2 Hz, 2H); 8.61 (s, 1H).

LC-MS: t _R=1.02 min, [M+H] ⁺=452.95.

1.ii. Benzyl-sulfamic acid [5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl]-amide

t-BuOK (18.5 g, 164.5 mmol) was added portionwise to a suspension of intermediate 1.i (7.46 g, 16.4 mmol) in ethylene glycol (50 mL). The mixture became warm and thick and was diluted with DME (75 mL). The mixture was stirred at 95° C. for 24 h before it was cooled to rt, diluted with water (50 mL) and a 10% aq. citric acid solution (250 mL). The milky suspension was extracted with EA (2×300 mL). The combined org. extracts were dried over MgSO ₄, filtered and the filtrate was concentrated. The remaining crystalline solid was suspended in MeOH, collected, washed well with MeOH and dried under HV to give the expected product as a white crystalline powder (6.49 g).

¹H NMR (CDCl ₃): δ 2.50 (t br., J=6 Hz, 1H); 3.80-3.88 (m, 2H); 4.20 (d, J=5.9 Hz, 2H); 4.46-4.50 (m, 2H); 5.99 (t br., J=6.4 Hz, 1H); 6.85 (s br., 1H); 7.12 (d, J=8.2 Hz, 2H); 7.23-7.34 (m, 5H); 7.64 (d, J=8.2 Hz, 2H); 8.44 (s, 1H).

LC-MS: t _R=0.93 min, [M+H] ⁺=479.08.

1.iii Benzyl-sulfamic acid [5-(4-bromophenyl)-6-{2-(5-bromo-pyrimidin-2-yloxy)-ethoxy}-pyrimidin-4-yl]-amide

To a solution of intermediate 1.ii (6.49 g, 13.5 mmol) in THF (120 mL) was added carefully NaH (1.77 g, 40.6 mmol, 55% dispersion in mineral oil). The mixture was stirred for 10 min before 2-chloro-5-bromo-pyrimidine (3.93 g, 20.3 mmol) was added. The mixture was diluted with DMF (15 mL) and then stirred at rt for 20 min. The mixture was heated to 60° C. and stirred for 3 h before being again cooled to rt. The reaction was quenched with water and 10% aq. citric acid solution (250 mL) and the mixture was extracted with EA (2×300 mL). The org. extracts were washed with water, combined, dried over MgSO ₄, filtered and the solvent of the filtrate was evaporated. The crude product was crystallised from MeOH/ether. The crystalline material was collected, washed with additional MeOH/ether and dried under HV to give the expected product as a white powder (6.47 g).

¹H NMR (CDCl ₃): δ 4.20 (d, J=6.4 Hz, 2H); 4.59-4.64 (m, 2H); 4.69-4.74 (m, 2H); 5.98 (t br., J=6.4 Hz, 1H); 6.83 (s br., 1H); 7.06-7.10 (m, 2H); 7.24-7.34 (m, 5H); 7.54-7.58 (m, 2H); 8.44 (s, 1H); 8.50 (s, 2H).

LC-MS: t _R=1.06 min, [M+H] ⁺=634.98.

1.iv. {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide

A solution of borontribromide (25.5 mL, 1 M in DCM) was slowly added to a solution of intermediate 1.iii (6.50 g, 10.2 mmol) in chloroform (250 mL). The mixture became turbid and an oily residue separated. The mixture was stirred at rt. Another portion of BBr ₃solution (5 mL) was added after 6, 24, and 33 h. After the last addition of BBr ₃, the beige suspension was stirred vigorously for additional 2 h before being carefully quenched with MeOH. The mixture became slightly warm and clear. The solution was washed with cold water (0° C., 2×150 mL). The washings were extracted back with DCM. The combined org. extracts were again washed with water, dried over MgSO ₄, filtered and concentrated. The crude product was purified by CC on silica gel eluting with heptane:EA 1:1 followed by crystallisation from DCM. The purified crystalline product was dried under HIV at 45° C. for 48 h to give the expected product as a white, crystalline powder (1.62 g).

¹H NMR (CDCl ₃): δ 4.60-4.65 (m, 2H), 4.71-4.74 (m, 2H), 5.50 (s br, 2H), 7.10 (s br, 1H), 7.13-7.17 (m, 2H), 7.55-7.59 (m, 2H), 8.49 (s, 2H), 8.50 (s, 1H).

LC-MS: t _R=0.93 min, [M+H] ⁺=544.70.

Clinical data

Trade names	Tryvio
Other names	ACT-132577
AHFS/Drugs.com	Tryvio
Routes of administration	By mouth
Drug class	Antihypertensive
ATC code	C02KN01 (WHO)
Legal status
Legal status	US: ℞-only^[1]
Identifiers
showIUPAC name
CAS Number	1103522-45-7
PubChem CID	25099191
IUPHAR/BPS	10070
DrugBank	DB15059
ChemSpider	25027753
UNII	MZI81HV01P
KEGG	D11441
ChEBI	CHEBI:76609
ChEMBL	ChEMBL2165326
Chemical and physical data
Formula	C₁₆H₁₄Br₂N₆O₄S
Molar mass	546.19 g·mol⁻¹
3D model (JSmol)	Interactive image
hideSMILESC1=CC(=CC=C1C2=C(N=CN=C2OCCOC3=NC=C(C=N3)Br)NS(=O)(=O)N)Br

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j “Tryvio- aprocitentan tablet, film coated”. DailyMed. 29 March 2024. Archived from the original on 25 April 2024. Retrieved 25 April 2024.
^ Jump up to:^a ^b ^c “US FDA approves Idorsia’s once-daily Tryvio (aprocitentan) – the first and only endothelin receptor antagonist for the treatment of high blood pressure not adequately controlled in combination with other antihypertensives” (Press release). Idorsia. 20 March 2024. Archived from the original on 28 April 2024. Retrieved 28 April 2024 – via PR Newswire.
^ Ojha, Utkarsh; Ruddaraju, Sanjay; Sabapathy, Navukkarasu; Ravindran, Varun; Worapongsatitaya, Pitchaya; Haq, Jeesanul; et al. (2022). “Current and Emerging Classes of Pharmacological Agents for the Management of Hypertension”. American Journal of Cardiovascular Drugs. 22 (3): 271–285. doi:10.1007/s40256-021-00510-9. PMC 8651502. PMID 34878631.
^ Jump up to:^a ^b Xu, Jingjing; Jiang, Xiaohua; Xu, Suowen (November 2023). “Aprocitentan, a dual endothelin-1 (ET-1) antagonist for treating resistant hypertension: Mechanism of action and therapeutic potential”. Drug Discovery Today. 28 (11): 103788. doi:10.1016/j.drudis.2023.103788. PMID 37742911.
^ “Novel Drug Approvals for 2024”. U.S. Food and Drug Administration (FDA). 29 April 2024. Archived from the original on 30 April 2024. Retrieved 30 April 2024.
^ Deswal, Phalguni (6 September 2023). “Idorsia reacquires aprocitentan rights from Janssen for $343m”. Pharmaceutical Technology. Archived from the original on 8 November 2023. Retrieved 8 November 2023.
^ Jump up to:^a ^b “Jeraygo EPAR”. European Medicines Agency. 25 April 2024. Archived from the original on 30 April 2024. Retrieved 27 April 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

Cefepime

May 17, 2024 6:23 am / Leave a comment

Cefepime

88040-23-7

INGREDIENT	UNII	CAS	INCHI KEY
Cefepime hydrochloride	I8X1O0607P	123171-59-5	LRAJHPGSGBRUJN-OMIVUECESA-N

Cefepime

CAS Registry Number: 88040-23-7

CAS Name: 1-[[(6R,7R)-7-[[(2Z)-(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methylpyrrolidinium inner salt

Additional Names: 1-[[(6R,7R)-7-[2-(2-amino-4-thiazolyl)glyoxylamido]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methylpyrrolidinium hydroxide inner salt 72-(Z)-2-(O-methyloxime); 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1-methylpyrrolidinio)methyl-3-cephem-4-carboxylate

Manufacturers’ Codes: BMY-28142

Molecular Formula: C19H24N6O5S2

Molecular Weight: 480.56

Percent Composition: C 47.49%, H 5.03%, N 17.49%, O 16.65%, S 13.34%

Literature References: Semisynthetic, fourth generation cephalosporin antibiotic. Prepn: S. Aburaki et al.,DE3307550; eidem,US4406899 (both 1983 to Bristol-Myers); and antibacterial activity: T. Naito et al.,J. Antibiot.39, 1092 (1986). In vitro comparative antimicrobial spectrum: N. J. Khan et al.,Antimicrob. Agents Chemother.26, 585 (1984); and b-lactamase stability: H. C. Neu et al.,J. Antimicrob. Chemother.17, 441 (1986). HPLC determn in plasma and urine: R. H. Barbhaiya et al.,Antimicrob. Agents Chemother.31, 55 (1987). Clinical evaluations in infection: N. Clynes et al.,Diagn. Microbiol. Infect. Dis.12, 257 (1989); S. Oster et al.,Antimicrob. Agents Chemother.34, 954 (1990). Review of clinical pharmacokinetics: M. P. Okamoto et al.,Clin. Pharmacokinet.25, 88-102 (1993).

Properties: Colorless powder, mp 150° (dec). uv max (pH 7 phosphate buffer): 235, 257 nm (e 16700, 16100).

Melting point: mp 150° (dec)

Absorption maximum: uv max (pH 7 phosphate buffer): 235, 257 nm (e 16700, 16100)

Derivative Type: Sulfate

Molecular Formula: C19H24N6O5S2.H2SO4

Molecular Weight: 578.64

Percent Composition: C 39.44%, H 4.53%, N 14.52%, O 24.89%, S 16.62%

Properties: mp 210° (dec). uv max (pH 7 phosphate buffer): 236, 258 nm (e 17200, 16900).

Melting point: mp 210° (dec)

Absorption maximum: uv max (pH 7 phosphate buffer): 236, 258 nm (e 17200, 16900)

Derivative Type: Hydrochloride monohydrate

CAS Registry Number: 123171-59-5

CAS Name: 1-[[(6R,7R)-7-[[(2Z)-(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methylpyrrolidinium chloride monohydrochloride monohydrate

Additional Names: cefepime hydrochloride

Trademarks: Axepim (BMS); Cepimex (Mead Johnson); Maxipime (BMS)

Molecular Formula: C19H25ClN6O5S2.HCl.H2O

Molecular Weight: 571.50

Percent Composition: C 39.93%, H 4.94%, Cl 12.41%, N 14.71%, O 16.80%, S 11.22%

Therap-Cat: Antibacterial.

Keywords: Antibacterial (Antibiotics); ?Lactams; Cephalosporins.

FDA APPROVED 2/22/2024, To treat complicated urinary tract infections, Exblifep

BMY 28142
BMY-28142

Cefepime is a fourth-generation cephalosporin antibiotic. Cefepime has an extended spectrum of activity against Gram-positive and Gram-negative bacteria, with greater activity against both types of organism than third-generation agents. A 2007 meta-analysis suggested when data of trials were combined, mortality was increased in people treated with cefepime compared with other β-lactam antibiotics.^[1] In response, the U.S. Food and Drug Administration (FDA) performed their own meta-analysis which found no mortality difference.^[2]

Cefepime was patented in 1982 by Bristol-Myers Squibb and approved for medical use in 1994.^[3] It is available as a generic drug and sold under a variety of trade names worldwide.^{[citation needed]}^[4]

It was removed from the World Health Organization’s List of Essential Medicines in 2019.^[5]

Medical use

Cefepime is usually reserved to treat moderate to severe nosocomial pneumonia, infections caused by multiple drug-resistant microorganisms (e.g. Pseudomonas aeruginosa) and empirical treatment of febrile neutropenia.^[6]

Cefepime has good activity against important pathogens including Pseudomonas aeruginosa, Staphylococcus aureus, and multiple drug-resistant Streptococcus pneumoniae. A particular strength is its activity against Enterobacteriaceae. Whereas other cephalosporins are degraded by many plasmid– and chromosome-mediated beta-lactamases, cefepime is stable and is a front-line agent when infection with Enterobacteriaceae is known or suspected.^{[medical citation needed]}

Spectrum of bacterial susceptibility

Cefepime is a broad-spectrum cephalosporin antibiotic and has been used to treat bacteria responsible for causing pneumonia and infections of the skin and urinary tract. Some of these bacteria include Pseudomonas, Escherichia, and Streptococcus species. The following represents MIC susceptibility data for a few medically significant microorganisms:^[7]

Escherichia coli: ≤0.007 – 128 μg/ml
Pseudomonas aeruginosa: 0.06 – >256 μg/ml
Streptococcus pneumoniae: ≤0.007 – >8 μg/ml

Chemistry

The combination of the syn-configuration of the methoxy imino moiety and the aminothiazole moiety confers extra stability to β-lactamase enzymes produced by many bacteria. The N–methyl pyrrolidine moiety increases penetration into Gram-negative bacteria. These factors increase the activity of cefepime against otherwise resistant organisms including Pseudomonas aeruginosa and Staphylococcus aureus.

Semisynthetic, fourth generation cephalosporin antibiotic. Prepn: S. Aburaki et al., DE 3307550; eidem, US 4406899 (both 1983 to Bristol-Myers); and antibacterial activity: T. Naito et al., J. Antibiot. 39, 1092 (1986).

Trade names

Following expiration of the Bristol-Myers Squibb patent,^[] cefepime became available as a generic and is now^] marketed by numerous companies worldwide under tradenames including Neopime (Neomed), Maxipime, Cepimax, Cepimex, and Axepim.

Clinical data


Pronunciation	/ˈsɛfɪpiːm/ or /ˈkɛfɪpiːm/
Trade names	Maxipime, Voco
AHFS/Drugs.com	Monograph
MedlinePlus	a698021
Pregnancy category	AU: B1
Routes of administration	Intravenous, intramuscular
ATC code	J01DE01 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)CA: ℞-onlyUK: POM (Prescription only)US: ℞-only
Pharmacokinetic data
Bioavailability	100% (IM)
Metabolism	Hepatic 15%
Elimination half-life	2 hours
Excretion	Renal 70–99%
Identifiers
showIUPAC name
CAS Number	88040-23-7
PubChem CID	5479537
DrugBank	DB01413
ChemSpider	4586395
UNII	807PW4VQE3
KEGG	D02376
ChEBI	CHEBI:478164
ChEMBL	ChEMBL186
CompTox Dashboard (EPA)	DTXSID70873208
ECHA InfoCard	100.171.025
Chemical and physical data
Formula	C₁₉H₂₄N₆O₅S₂
Molar mass	480.56 g·mol⁻¹
3D model (JSmol)	Interactive image
Melting point	150 °C (302 °F) (dec.)
showSMILES
showInChI
(verify)

References

^ Yahav D, Paul M, Fraser A, Sarid N, Leibovici L (May 2007). “Efficacy and safety of cefepime: a systematic review and meta-analysis”. The Lancet. Infectious Diseases. 7 (5): 338–348. doi:10.1016/S1473-3099(07)70109-3. PMID 17448937.
^ “FDA Alert: Cefepime (marketed as Maxipime)”. Information for Healthcare Professionals. Food and Drug Administration. Archived from the original on 2 November 2017. Retrieved 2 August 2009.
^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 496. ISBN 9783527607495. Archived from the original on 19 June 2021. Retrieved 19 September 2020.
^ “Cefepime (maxipime), large spectrum 4th generation cephalosporin, resistant to beta-lactamases]”.
^ World Health Organization (2019). Executive summary: the selection and use of essential medicines 2019: report of the 22nd WHO Expert Committee on the selection and use of essential medicines. Geneva: World Health Organization. hdl:10665/325773. WHO/MVP/EMP/IAU/2019.05. License: CC BY-NC-SA 3.0 IGO.
^ Chapman TM, Perry CM (2003). “Cefepime: a review of its use in the management of hospitalized patients with pneumonia”. American Journal of Respiratory Medicine. 2 (1): 75–107. doi:10.1007/bf03256641. PMID 14720024.
^ “Cefepime Susceptibility and Concentration Range (μg/ml) Minimum Inhibitory Concentration (MIC) Data” (PDF). The Antimicrobial Index. toku-e.com. Archived from the original (PDF) on 1 November 2018.

External links

“Cefepime”. Drug Information Portal. U.S. National Library of Medicine.

//////////cefepime, Exblifep, FDA 2024, APPROVALS 2024, BMY 28142, BMY-28142

Berdazimer

May 14, 2024 8:33 am / Leave a comment

Berdazimer

1846565-00-1

CAS NA SALT, 1846565-00-1

FDA APPROVE 1 /5/2024, To treat molluscum contagiosum
Drug Trials Snapshot

NVN-1000 free acid
NVN1000 free acid
Silsesquioxanes, 3-(2-hydroxy-1-methyl-2-nitrosohydrazinyl)propyl 3-(methylamino)propyl, polymers with silicic acid (h4sio4) tetra-et ester, hydroxy-terminated

Berdazimer sodium, sold under the brand name Zelsuvmi, is a medication used for the treatment for molluscum contagiosum.^[1] Berdazimer sodium is a nitric oxide releasing agent.^[1] It is a polymer formed from sodium 1-hydroxy-3-methyl-3-(3-(trimethoxysilyl)propyl)-1-triazene-2-oxide and tetraethyl silicate.^[2]

Berdazimer sodium was approved for medical use in the United States in January 2024.^[3]^[4]^[5]

Medical uses

Berdazimer sodium is indicated for the topical treatment of molluscum contagiosum.^[1]

Pharmacology

Mechanism of action

Berdazimer sodium is a nitric oxide releasing agent.^[1] The mechanism of action for the treatment of molluscum contagiosum is unknown.^[1]

Pharmacodynamics

The pharmacodynamics of berdazimer sodium are unknown.^[1]

Society and culture

Legal status

Berdazimer sodium was approved for medical use in the United States in January 2024.^[4]

Names

Berdazimer sodium is the international nonproprietary name.^[6]

Berdazimer

Berdazimer is a polymeric substance consisting of a polysiloxane backbone (Si-O-Si bonds) with covalently bound N-diazeniumdiolate nitric oxide (NO) donors. It releases NO through exposure to proton donors like water, which will degrade the N-diazeniumdiolate entity.² Berdazimer was previously investigated as a potential treatment for molluscum contagiosum, a viral cutaneous infection mainly affecting children, sexually active adults, and immunocompromised patients. It is one of the 5 most prevalent skin diseases in the world and the third-most common viral skin infection in children.³ Previously, the first line treatment for molluscum contagiosum was surgical excision, although it poses challenges such as repeated doctor visits, post-surgical scarring and skin discoloration, and fear and anxiety in the pediatric population.³

On Jan 05, 2024, the FDA approved berdazimer under the brand name ZELSUVMI for the treatment of adult and pediatric molluscum contagiosum, and it is the first drug to be approved for this condition. This decision is based on positive results demonstrated in 2 Phase 3 trials, B-SIMPLE 4 and B-SIMPLE 2, where reduced lesion counts were observed with once-a-day uses of berdazimer.⁵

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ “Zelsuvmi (berdazimer) topical gel” (PDF). Archived (PDF) from the original on 19 January 2024. Retrieved 9 January 2024.
^ “GSRS”. gsrs.ncats.nih.gov. Archived from the original on 8 January 2024. Retrieved 8 January 2024.
^ “Drug Approval Package: Zelsuvmi”. U.S. Food and Drug Administration (FDA). 2 February 2024. Archived from the original on 11 March 2024. Retrieved 11 March 2024.
^ Jump up to:^a ^b “Novel Drug Approvals for 2024”. U.S. Food and Drug Administration (FDA). 29 April 2024. Archived from the original on 30 April 2024. Retrieved 30 April 2024.
^ “U.S. Food and Drug Administration Approves Zelsuvmi as a First-in-Class Medication for the Treatment of Molluscum Contagiosum”. Ligand Pharmaceuticals. 5 January 2024. Archived from the original on 8 January 2024. Retrieved 8 January 2024 – via Business Wire.
^ World Health Organization (2018). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 79”. WHO Drug Information. 32 (1). hdl:10665/330941.

External links

“Berdazimer Sodium (Code C174810)”. NCI Thesaurus.
Clinical trial number NCT04535531 for “A Phase 3 Molluscum Contagiosum Efficacy and Safety Study (B-SIMPLE4)” at ClinicalTrials.gov
Clinical trial number NCT03927703 for “A Phase 3 Efficacy & Safety of SB206 & Vehicle Gel for the Treatment of MC (B-SIMPLE2)” at ClinicalTrials.gov
Clinical trial number NCT03927716 for “A Phase 3 Randomized Parallel Group Study Comparing the Efficacy & Safety of SB206 & Vehicle Gel in the Treatment of MC (B-SIMPLE1)” at ClinicalTrials.gov

Clinical data

Trade names	Zelsuvmi
Other names	SB206
License data	US DailyMed: Berdazimer sodium
Routes of administration	Topical
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
CAS Number	1846565-00-1
DrugBank	DBSALT003491 DB18712
UNII	ORT9SID4QY B23P7SM943
KEGG	D12758
ChEMBL	ChEMBL4298064
Chemical and physical data
Formula	Indeterminate^[1]
Molar mass	Indeterminate^[1]

/////Berdazimer, Zelsuvmi, FDA 2024, APPROVALS 2024, NVN-1000 free acid, NVN1000 free acid

Tovorafenib

May 10, 2024 2:50 am / Leave a comment

(r)-2-(1-(6-Amino-5-chloropyrimidine-4-carboxamido)ethyl)-n-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-carboxamide.png

Tovorafenib

506.29

C₁₇H₁₂Cl₂F₃N₇O₂S

1096708-71-2

6-amino-5-chloro-N-[(1R)-1-(5-{[5-chloro-4-(trifluoromethyl)pyridin-2-yl]carbamoyl}-1,3-thiazol-2-yl)ethyl]pyrimidine-4-carboxamide

4/23/2024 FDA APROVED, To treat relapsed or refractory pediatric low-grade glioma, Ojemda

AMG 2112819
BIIB 024
BIIB-024
BIIB024
DAY 101
DAY-101
DAY101
MLN 2480
MLN-2480
MLN2480
TAK 580
TAK-580
TAK580

Tovorafenib, sold under the brand name Ojemda, is a medication used for the treatment of glioma.^[1] It is a kinase inhibitor.^[1]

The most common adverse reactions include rash, hair color changes, fatigue, viral infection, vomiting, headache, hemorrhage, pyrexia, dry skin, constipation, nausea, dermatitis acneiform, and upper respiratory tract infection.^[2] The most common grade 3 or 4 laboratory abnormalities include decreased phosphate, decreased hemoglobin, increased creatinine phosphokinase, increased alanine aminotransferase, decreased albumin, decreased lymphocytes, decreased leukocytes, increased aspartate aminotransferase, decreased potassium, and decreased sodium.^[2]

It was approved for medical use in the United States in April 2024,^[1]^[2]^[3]^[4] and is the first approval of a systemic therapy for the treatment of people with pediatric low-grade glioma with BRAF rearrangements, including fusions.^[2]

Medical uses

Tovorafenib is indicated for the treatment of people six months of age and older with relapsed or refractory pediatric low-grade glioma harboring a BRAF fusion or rearrangement, or BRAF V600 mutation.^[1]^[2]

History

Efficacy was evaluated in 76 participants enrolled in FIREFLY-1 (NCT04775485), a multicenter, open-label, single-arm trial in participants with relapsed or refractory pediatric low-grade glioma harboring an activating BRAF alteration detected by a local laboratory who had received at least one line of prior systemic therapy.^[2] Participants were required to have documented evidence of radiographic progression and at least one measurable lesion.^[2] Participants with tumors harboring additional activating molecular alterations (e.g., IDH1/2 mutations, FGFR mutations) or with a known or suspected diagnosis of neurofibromatosis type 1 were excluded.^[2] Participants received tovorafenib based on body surface area (range: 290 to 476 mg/m2, up to a maximum dose of 600 mg) once weekly until they experienced disease progression or unacceptable toxicity.^[2] The US Food and Drug Administration (FDA) granted the application for tovorafenib priority review, breakthrough therapy, and orphan drug designations.^[2]

Society and culture

Names

Tovorafenib is the international nonproprietary name.^[5]

SYN

PATENT

WO 2009/006389

Huang et al., Angew. Chem. int. Ed. (2016), 55, 5309-5317

Jiang Xiao-bin et al., Org. Lett. (2003), 5, 1503

https://patentscope.wipo.int/search/en/detail.jsf?docId=US43216699&_cid=P22-LW02JF-43766-1

10Da

(R)-2-(1-(6-amino-5-chloropyrimidine-4- carboxamido)ethyl)-N-(5-chloro-4- (trifluoromethyl)pyridin-2-yl)thiazole-5- carboxamide

SYN

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2009006389&_cid=P22-LW025M-38416-1

Patent

https://patentscope.wipo.int/search/en/detail.jsf?docId=US131345763&_cid=P22-LW02NH-45076-1

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US201396258&_cid=P22-LW02NH-45076-1

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=EP292571929&_cid=P22-LW02NH-45076-1

References

^ Jump up to:^a ^b ^c ^d ^e “Archived copy” (PDF). Archived (PDF) from the original on 24 April 2024. Retrieved 24 April 2024.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j “FDA grants accelerated approval to tovorafenib for patients with relapsed or refractory BRAF-altered pediatric low-grade glioma”. U.S. Food and Drug Administration (FDA). 23 April 2024. Archived from the original on 23 April 2024. Retrieved 25 April 2024. This article incorporates text from this source, which is in the public domain.
^ “Novel Drug Approvals for 2024”. U.S. Food and Drug Administration (FDA). 29 April 2024. Archived from the original on 30 April 2024. Retrieved 30 April 2024.
^ “Day One’s Ojemda (tovorafenib) Receives US FDA Accelerated Approval for Relapsed or Refractory BRAF-altered Pediatric Low-Grade Glioma (pLGG), the Most Common Form of Childhood Brain Tumor”. Day One Biopharmaceuticals (Press release). 23 April 2024. Archived from the original on 23 April 2024. Retrieved 24 April 2024.
^ World Health Organization (2022). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 88”. WHO Drug Information. 36 (3). hdl:10665/363551.

External links

“Tovorafenib”. NCI Drug Dictionary.
“Tovorafenib (Code C106254)”. NCI Thesaurus.
Clinical trial number NCT04775485 for “A Study to Evaluate DAY101 in Pediatric and Young Adult Patients With Relapsed or Progressive Low-Grade Glioma and Advance Solid Tumors (FIREFLY-1)” at ClinicalTrials.gov

Clinical data

Trade names	Ojemda
Other names	BIIB-024, MLN2480, AMG 2112819, DAY101, TAK-580
License data	US DailyMed: Tovorafenib
Routes of administration	By mouth
Drug class	Antineoplastic
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
showIUPAC name
CAS Number	1096708-71-2
PubChem CID	25161177
DrugBank	DB15266
ChemSpider	28637796
UNII	ZN90E4027M
KEGG	D12291
ChEBI	CHEBI:167672
ChEMBL	ChEMBL3348923
PDB ligand	QOP (PDBe, RCSB PDB)
Chemical and physical data
Formula	C₁₇H₁₂Cl₂F₃N₇O₂S
Molar mass	506.29 g·mol⁻¹
showInChI

////////Tovorafenib, Ojemda, FDA 2024. APPROVALS 2024, AMG 2112819, BIIB 024, BIIB-024, BIIB024, DAY 101, DAY-101, DAY101, MLN 2480, MLN-2480, MLN2480, TAK 580, TAK-580, TAK580

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EXAMPLE

Preparation A: Benzylsulfamide Potassium Salt

A.i. Benzylsulfamide

A.ii. Benzylsulfamide Potassium Salt

Preparation B: 5-(4-bromo-phenyl)-4,6-dichloro-pyrimidine

B.i. 4-bromophenylacetic acid methyl ester

B.ii. 2-(4-bromophenyl)-malonic acid dimethyl ester

B.iii. 5-(4-bromophenyl)-pyrimidine-4,6-diol

B.iv. 5-(4-bromo-phenyl)-4,6-dichloro-pyrimidine

Example 1

{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide

1.i. Benzyl-sulfamic acid [6-chloro-5-(4-bromophenyl)-pyrimidin-4-yl]-amide

1.ii. Benzyl-sulfamic acid [5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl]-amide

1.iii Benzyl-sulfamic acid [5-(4-bromophenyl)-6-{2-(5-bromo-pyrimidin-2-yloxy)-ethoxy}-pyrimidin-4-yl]-amide

1.iv. {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide

References

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Following expiration of the Bristol-Myers Squibb patent,[] cefepime became available as a generic and is now] marketed by numerous companies worldwide under tradenames including Neopime (Neomed), Maxipime, Cepimax, Cepimex, and Axepim.

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Following expiration of the Bristol-Myers Squibb patent,^[] cefepime became available as a generic and is now^] marketed by numerous companies worldwide under tradenames including Neopime (Neomed), Maxipime, Cepimax, Cepimex, and Axepim.