"目录号: HY-15298
Metabolic Enzyme/ProteaseAnti-infection-
MK-5172 是一种选择性的丙型肝炎病毒 NS3/4a 蛋白酶抑制剂，作用于 gt1b，gt1a，gt2a，gt2b 和 gt3a，Ki分别为 0.01 nM，0.01 nM，0.08 nM，0.15 nM 和 0.90 nM。
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Asunaprevir-PSI-7977-Simeprevir-Daclatasvir-Paritaprevir-Telaprevir-Boceprevir-Ledipasvir-Ombitasvir-Elbasvir-ABT-333-Ribavirin-R-1479-Balapiravir-Artemisinin-
生物活性
Description
MK-5172 is a selective inhibitor ofHepatitis C virus NS3/4aprotease with broad activity across genotypes and resistant variants, withKiof 0.01 nM (gt1b), 0.01 nM (gt1a), 0.08 nM (gt2a), 0.15 nM (gt2b), 0.90 nM (gt3a), respectively.
IC50& Target
Ki: 0.01±<0.01 nM (gt1b), 0.01±0.01 nM (gt1a), 0.08±0.02 nM (gt2a), 0.15±0.06 nM (gt2b), 0.90±0.2 nM (gt3a)[1]
In Vitro
In biochemical assays, MK-5172 is effective against a panel of major genotypes and variants engineered with common resistant mutations, with Kiof 0.01±<0.01 nM (gt1b), 0.01±0.01 nM (gt1a), 0.08±0.02 nM (gt2a), 0.15±0.06 nM (gt2b), 0.90±0.2 nM (gt3a), 0.07±0.01 nM (gt1bR155K), 0.14±0.03 nM (gt1bD168V), 0.30±0.04 nM (gt1bD168Y), 5.3±0.9 nM (gt1bA156T), and 12±2 nM (gt1bA156V), respectively. In the replicon assay, MK-5172 demonstrates subnanomolar to low-nanomolar EC50s against genotypes 1a, 1b, and 2a, with EC50s of 0.5±0.1 nM, 2±1 nM, and 2±1 nM for gt1bcon1, gt1a, and gt2a, respectively. MK-5172 is potent against a panel of HCV replication mutants NS5A (Y93H) (EC50=0.7±0.3 nM), NS5B nucleosides (S282T) (EC50=0.3±0.1 nM), and NS5B (C316Y) (EC50=0.4±0.2)[1]. MK-5172 maintains the excellent potency against the gt 3a enzyme as well as a broad panel of mutant enzymes, has excellent potency in the replicon system [gt1b IC50(50% NHS)=7.4 nM; gt1a IC50(40% NHS)=7 nM], and shows excellent rat liver exposure[2].
In Vivo
MK-5172 demonstrates efficacy in vivo against chronic-HCV-infected chimpanzees[1]. When dosed to dogs, MK-5172 shows low clearance of 5 mL/min/kg and a 3 h half-life after iv dosing and has good plasma exposure (AUC=0.4 μM h) after a 1 mg/kg oral dose. Dog liver biopsy studies showed that the liver concentration of MK-5172 after the 1 mg/kg oral dose is 1.4 μM at the 24 h time point. Similar to its behavior in rats, MK-5172 demonstrates effective partitioning into liver tissue and maintains high liver concentration, relative to potency, 24 h after oral dosing in dogs[2].
Clinical Trial
Kyushu University-Merck Sharp & Dohme Corp.
Hepatitis C Viral-Chronic Kidney Disease stage3
April 1, 2017
Phase 4
University Hospital, Clermont-Ferrand-Merck Sharp & Dohme Corp.-LC2 PHARMA
Chronic HCV Infection
November 2016
Phase 3
Merck Sharp & Dohme Corp.
Chronic Hepatitis C
June 2014
Phase 3
Taoyuan General Hospital-Merck Sharp & Dohme Corp.
To Assess the Efficacy of Grazoprevir 100mg and Elbasvir 50mg by Determining the Proportion of Sustained Virological Response 12 Weeks After the End of Therapy
June 20, 2017
Phase 4
Kirby Institute
Hepatitis C
December 2016
Phase 4
Merck Sharp & Dohme Corp.
Hepatitis C
October 2013
Phase 1
Institute Of Cardiology & Internal Diseases, Kazakhstan-Schering-Plough-Synergy Research Group
Chronic Hepatitis C Genotype 1B-Metabolic Syndrome-Fibrosis, Liver-Cirrhoses, Liver
October 2017
Phase 3
Merck Sharp & Dohme Corp.
Hepatitis C
October 17, 2012
Erasmus Medical Center
Acute Hepatitis C-Human Immunodeficiency Virus-Hepatitis C
February 2016
Phase 3
Merck Sharp & Dohme Corp.
Chronic Hepatitis C
September 2, 2014
Phase 3
Merck Sharp & Dohme Corp.
Hepatitis C, Chronic
November 2011
Phase 2
University Hospital, Toulouse-MSD France
Hepatitis C-Chronic Kidney Diseases
June 2, 2017
Merck Sharp & Dohme Corp.
Hepatitis C
February 2010
Phase 1
Merck Sharp & Dohme Corp.
Hepatitis C Infection
June 2014
Phase 3
Merck Sharp & Dohme Corp.
Hepatitis C
January 28, 2015
Phase 3
Massachusetts General Hospital-Merck Sharp & Dohme Corp.
Renal Failure
February 1, 2017
Phase 4
Merck Sharp & Dohme Corp.
Hepatitis C
January 2013
Phase 2
Merck Sharp & Dohme Corp.
Hepatitis C
June 2014
Phase 2
University of Maryland
Hepatitis C-Renal Insufficiency, Chronic-Disorder of Transplanted Kidney
May 1, 2017
Phase 4
Merck Sharp & Dohme Corp.
Chronic Hepatitis C (CHC)
December 2012
Phase 2
Norte Study Group-Merck Sharp & Dohme Corp.
Chronic Hepatitis C
January 15, 2017
Phase 4
Merck Sharp & Dohme Corp.
Hepatitis C
July 2011
Phase 1
Institut de Médecine et d'Epidémiologie Appliquée - Fondation Internationale Léon M'Ba-Merck Sharp & Dohme Corp.-Institut National de la Santé Et de la Recherche Médicale, France
Acute Hepatitis C-HIV
May 24, 2017
Phase 2
Merck Sharp & Dohme Corp.
Hepatitis C
October 22, 2014
Phase 3
French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
Hepatitis C
January 2016
Phase 2
Hepa C
Hepatitis C
March 31, 2017
Merck Sharp & Dohme Corp.
Hepatitis C Virus
March 2014
Phase 2-Phase 3
Raymond T. Chung, MD-Merck Sharp & Dohme Corp.-Massachusetts General Hospital
Cardiac Transplant Disorder-Hepatitis C
December 1, 2017
Phase 4
Merck Sharp & Dohme Corp.
Chronic Hepatitis C
May 2012
Phase 1
Merck Sharp & Dohme Corp.
Chronic Hepatitis C-Renal Impairment
September 2013
Phase 1
Merck Sharp & Dohme Corp.
Hepatitis C
October 2013
Phase 2
Merck Sharp & Dohme Corp.
Chronic Hepatitis C
May 2014
Phase 2-Phase 3
Merck Sharp & Dohme Corp.
Hepatitis C
November 2014
Phase 3
Merck Sharp & Dohme Corp.
Hepatitis C
February 27, 2015
Phase 3
Merck Sharp & Dohme Corp.
Chronic Hepatitis C Virus
June 2014
Phase 3
Merck Sharp & Dohme Corp.
Hepatitis C
January 2016
Phase 2
Merck Sharp & Dohme Corp.
Hepatitis C
August 2014
Phase 2-Phase 3
Tel-Aviv Sourasky Medical Center-Merck Sharp & Dohme Corp.
HCV, HCC
May 1, 2017
Merck Sharp & Dohme Corp.
Hepatitis C
February 2013
Phase 2
Merck Sharp & Dohme Corp.
Hepatitis C Virus
May 2014
Phase 2
Merck Sharp & Dohme Corp.
Hepatitis C
January 22, 2015
Phase 2
Merck Sharp & Dohme Corp.
Hepatitis C
January 28, 2015
Phase 2
Fundacion SEIMC-GESIDA
HCV
July 15, 2017
Phase 4
Merck Sharp & Dohme Corp.
Hepatitis C, Chronic
June 2011
Phase 2
University of Zurich
Hepatitis C-HIV
June 2016
Phase 3
Funda
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