MK-5172 hydrate

Category	HCV Protease
CAS	1350462-55-3
Description	In biochemical assays, MK-5172 was effective against a panel of major genotypes and variants engineered with common resistant mutations observed in clinical studies with other NS3/4a protease inhibitors. In the replicon assay, MK-5172 demonstrated subnanomolar to low-nanomolar EC50s against genotypes 1a, 1b, and 2a. In rats, MK-5172 showed a plasma clearance of 28 ml/min/kg and plasma half-life of 1.4 hr. When dosed p.o. at 5 mg/kg, the plasma exposure of MK-5172 was good with an AUC of 0.7 uM.hr. The liver exposure of the compound was quite good (23 uM at 4 hr), and MK-5172 remained in liver 24 hr after a single p.o. 5 mg/kg dose. At 24 hr, the liver concentration of MK-5172 was 0.2 uM, which was over 25-fold higher than the IC50 in the replicon assay with 50% NHS. When dosed to dogs, MK-5172 showed low clearance of 5 ml/min/kg and a 3 hr half-life after i.v. 2 mg/kg dosing and had good plasma exposure (AUC=0.4 uM.hr) after a p.o. 1 mg/kg dose.

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Product Information

Synonyms	(33R,35S,91R,92R,5S)-5-(tert-butyl)-N-((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-17-methoxy-4,7-dioxo-2,8-dioxa-6-aza-1(2,3)-quinoxalina-3(3,1)-pyrrolidina-9(1,2)-cyclopropanacyclotetradecaphane-35-carboxamide hydrate; MK-5172; MK 5172; MK5172; Grazoprevir; Grazoprevir hydrate; trade name: Zepatier‎
IUPAC Name	(1R,18R,20R,24S,27S)-24-tert-butyl-N-[(1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-ethenylcyclopropyl]-7-methoxy-22,25-dioxo-2,21-dioxa-4,11,23,26-tetrazapentacyclo[24.2.1.03,12.05,10.018,20]nonacosa-3,5(10),6,8,11-pentaene-27-carboxamide;hydrate
Molecular Weight	784.92
Molecular Formula	C38H52N6O10S
Canonical SMILES	O=C([C@H]1N(C2)C([C@H](C(C)(C)C)NC(O[C@@]3([H])[C@](C3)([H])CCCCCC4=NC5=CC=C(OC)C=C5N=C4O[C@]2([H])C1)=O)=O)N[C@@]6(C(NS(=O)(C7CC7)=O)=O)[C@H](C=C)C6.[H]O[H]
InChI	1S/C38H50N6O9S.H2O/c1-6-22-19-38(22,35(47)43-54(49,50)25-13-14-25)42-32(45)29-18-24-20-44(29)34(46)31(37(2,3)4)41-36(48)53-30-16-21(30)10-8-7-9-11-27-33(52-24)40-28-17-23(51-5)12-15-26(28)39-27;/h6,12,15,17,21-22,24-25,29-31H,1,7-11,13-14,16,18-20H2,2-5H3,(H,41,48)(H,42,45)(H,43,47);1H2/t21-,22-,24-,29+,30-,31-,38-;/m1./s1
InChIKey	RXSARIJMSJWJLZ-CIAYNJNFSA-N
Purity	>98%
Solubility	In Vitro: DMSO : 50 mg/mL(63.70 mM;Need ultrasonic) In Vivo: 1.Add each solvent one by one:10% DMSO >> 40%PEG300 >> 5%Tween-80 >> 45% saline Solubility: ≥ 2.5 mg/mL (3.19 mM); Clear solution 2.Add each solvent one by one:10% DMSO >> 90%corn oil Solubility: ≥ 2.5 mg/mL (3.19 mM); Clear solution
Appearance	White to off-white solid powder
Application	Antiviral Agents
Storage	Dry, dark and at 0 - 4 C for short term (days to weeks) or -23 C for long term (months to years).
Animal Admin	In biochemical analysis, Grazoprevir (MK-5172) was effective against a group of major genotypes and variants with common resistance mutations with a Ki of 0.01±<0.01 nM (gt1b), 0.01±0.01 nM (gt1a), 0.08±0.02 nM (gt2a), 0.15±0.06nM (gt2b), 0.90±0.2nM (gt3a), and 0.07 ± 0.01nM(gt1bR155K), 0.14±0.03nM(gt1bD168V), 0.30±0.04nM (gt1bD168Y), 5.3±0.9nM (gt1bA156T) 12±2nM(gt1bA156V), respectively. In the replicon assay, Grazoprevir showed subnanomolar to low nanomolar EC50 for genotypes 1a, 1b, and 2a, and EC50s of 0.5±0.1nM, 2±1nM, and 2±1nM, respectively, for gt1bcon1, gt1a, and gt2a. Grazoprevir is valid against a group of HCV replication mutants NS5A (Y93H) (EC50 = 0.7±0.3 nM), NS5B nucleoside (S282T) (EC50 = 0.3±0.1 nM), and NS5B (C316Y) (EC50 = 0.4±0.2). Grazoprevir (MK-5172) maintains excellent potency against gt 3a enzyme as well as a broad group of mutant enzymes, with excellent potency in replicons [gt1b IC50 (50% NHS) = 7.4 nM; gtaa IC50 (40% NHS) = 7 nM], showing excellent rat liver exposure.
Complexity	1580
Exact Mass	784.34656305
In Vitro	In biochemical analysis, Grazoprevir (MK-5172) was effective against a group of major genotypes and variants with common resistance mutations with a Ki of 0.01±<0.01 nM (gt1b), 0.01±0.01 nM (gt1a), 0.08±0.02 nM (gt2a), 0.15±0.06nM (gt2b), 0.90±0.2nM (gt3a), and 0.07 ± 0.01nM(gt1bR155K), 0.14±0.03nM(gt1bD168V), 0.30±0.04nM (gt1bD168Y), 5.3±0.9nM (gt1bA156T) 12±2nM(gt1bA156V), respectively. In the replicon assay, Grazoprevir showed subnanomolar to low nanomolar EC50 for genotypes 1a, 1b, and 2a, and EC50s of 0.5±0.1nM, 2±1nM, and 2±1nM, respectively, for gt1bcon1, gt1a, and gt2a. Grazoprevir is valid against a group of HCV replication mutants NS5A (Y93H) (EC50 = 0.7±0.3 nM), NS5B nucleoside (S282T) (EC50 = 0.3±0.1 nM), and NS5B (C316Y) (EC50 = 0.4±0.2). Grazoprevir (MK-5172) maintains excellent potency against gt 3a enzyme as well as a broad group of mutant enzymes, with excellent potency in replicons [gt1b IC50 (50% NHS) = 7.4 nM; gtaa IC50 (40% NHS) = 7 nM], showing excellent rat liver exposure.
In Vivo	Grazoprevir (MK-5172) is effective in vivo against chronically HCV-infected chimpanzees. When administered to dogs, Grazoprevir (MK-5172) showed a low clearance of 5 mL / min / kg after intravenous administration and a half-life of 3 h with good plasma exposure (AUC = 0.4 μMh) dose after 1 mg / kg oral dose. Dog liver biopsy studies have shown that the liver concentration of Grazoprevir after 1 mg/kg oral dose is 1.4 μM at a 24 h time point. Similar to its behavior in rats, Grazoprevir demonstrates effective distribution into liver tissue and maintains high liver concentrations relative to potency for 24 h after oral administration in dogs.
PSA	223.30000
Target	HCV; HCV Protease; SARS-CoV