MK-5172

"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。

HCV ProteaseHCV

相关产品

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

NCT03144635

Kyushu University-Merck Sharp & Dohme Corp.

Hepatitis C Viral-Chronic Kidney Disease stage3

April 1, 2017

Phase 4

NCT02973503

University Hospital, Clermont-Ferrand-Merck Sharp & Dohme Corp.-LC2 PHARMA

Chronic HCV Infection

November 2016

Phase 3

NCT02105662

Merck Sharp & Dohme Corp.

Chronic Hepatitis C

June 2014

Phase 3

NCT03098121

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

NCT02940691

Kirby Institute

Hepatitis C

December 2016

Phase 4

NCT01537900

Merck Sharp & Dohme Corp.

Hepatitis C

October 2013

Phase 1

NCT03222167

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

NCT01667081

Merck Sharp & Dohme Corp.

Hepatitis C

October 17, 2012

NCT02600325

Erasmus Medical Center

Acute Hepatitis C-Human Immunodeficiency Virus-Hepatitis C

February 2016

Phase 3

NCT02105688

Merck Sharp & Dohme Corp.

Chronic Hepatitis C

September 2, 2014

Phase 3

NCT01440595

Merck Sharp & Dohme Corp.

Hepatitis C, Chronic

November 2011

Phase 2

NCT03145623

University Hospital, Toulouse-MSD France

Hepatitis C-Chronic Kidney Diseases

June 2, 2017

NCT00998985

Merck Sharp & Dohme Corp.

Hepatitis C

February 2010

Phase 1

NCT02105701

Merck Sharp & Dohme Corp.

Hepatitis C Infection

June 2014

Phase 3

NCT02251990

Merck Sharp & Dohme Corp.

Hepatitis C

January 28, 2015

Phase 3

NCT02945150

Massachusetts General Hospital-Merck Sharp & Dohme Corp.

Renal Failure

February 1, 2017

Phase 4

NCT01716156

Merck Sharp & Dohme Corp.

Hepatitis C

January 2013

Phase 2

NCT02133131

Merck Sharp & Dohme Corp.

Hepatitis C

June 2014

Phase 2

NCT02902120

University of Maryland

Hepatitis C-Renal Insufficiency, Chronic-Disorder of Transplanted Kidney

May 1, 2017

Phase 4

NCT01710501

Merck Sharp & Dohme Corp.

Chronic Hepatitis C (CHC)

December 2012

Phase 2

NCT03022006

Norte Study Group-Merck Sharp & Dohme Corp.

Chronic Hepatitis C

January 15, 2017

Phase 4

NCT01390428

Merck Sharp & Dohme Corp.

Hepatitis C

July 2011

Phase 1

NCT02886624

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

NCT02252016

Merck Sharp & Dohme Corp.

Hepatitis C

October 22, 2014

Phase 3

NCT02647632

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

NCT03111966

Hepa C

Hepatitis C

March 31, 2017

NCT02092350

Merck Sharp & Dohme Corp.

Hepatitis C Virus

March 2014

Phase 2-Phase 3

NCT03026023

Raymond T. Chung, MD-Merck Sharp & Dohme Corp.-Massachusetts General Hospital

Cardiac Transplant Disorder-Hepatitis C

December 1, 2017

Phase 4

NCT01547312

Merck Sharp & Dohme Corp.

Chronic Hepatitis C

May 2012

Phase 1

NCT01937975

Merck Sharp & Dohme Corp.

Chronic Hepatitis C-Renal Impairment

September 2013

Phase 1

NCT01932762

Merck Sharp & Dohme Corp.

Hepatitis C

October 2013

Phase 2

NCT02115321

Merck Sharp & Dohme Corp.

Chronic Hepatitis C

May 2014

Phase 2-Phase 3

NCT02204475

Merck Sharp & Dohme Corp.

Hepatitis C

November 2014

Phase 3

NCT02358044

Merck Sharp & Dohme Corp.

Hepatitis C

February 27, 2015

Phase 3

NCT02105467

Merck Sharp & Dohme Corp.

Chronic Hepatitis C Virus

June 2014

Phase 3

NCT02601573

Merck Sharp & Dohme Corp.

Hepatitis C

January 2016

Phase 2

NCT02203149

Merck Sharp & Dohme Corp.

Hepatitis C

August 2014

Phase 2-Phase 3

NCT03110055

Tel-Aviv Sourasky Medical Center-Merck Sharp & Dohme Corp.

HCV, HCC

May 1, 2017

NCT01717326

Merck Sharp & Dohme Corp.

Hepatitis C

February 2013

Phase 2

NCT02105454

Merck Sharp & Dohme Corp.

Hepatitis C Virus

May 2014

Phase 2

NCT02332707

Merck Sharp & Dohme Corp.

Hepatitis C

January 22, 2015

Phase 2

NCT02332720

Merck Sharp & Dohme Corp.

Hepatitis C

January 28, 2015

Phase 2

NCT03105349

Fundacion SEIMC-GESIDA

HCV

July 15, 2017

Phase 4

NCT01353911

Merck Sharp & Dohme Corp.

Hepatitis C, Chronic

June 2011

Phase 2

NCT02785666

University of Zurich

Hepatitis C-HIV

June 2016

Phase 3

NCT02897596

Funda

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