Inhibitors of hepatitis C virus NS3/4A: α-Ketoamide based macrocyclic inhibitors

被引：16

作者：

Avolio, Salvatore ^{[1
]}

Robertson, Keith ^{[1
]}

Hernando, Jose Ignacio Martin ^{[1
]}

DiMuzio, Jillian ^{[2
]}

Summa, Vincenzo ^{[1
]}

机构：

[1] IRBM Merck Res Labs Rome, I-00040 Rome, Italy

[2] Merck Res Labs, West Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 08期

关键词：

Hepatitis C; NS3 serine protease; alpha-Ketoamide; Macrocycle; PK properties; PROTEASE INHIBITOR; ANTIVIRAL ACTIVITY; SERINE-PROTEASE; OXIDATION; DISCOVERY; INTERFERON; SCH-503034; MECHANISM; COVALENT; ALCOHOLS;

D O I：

10.1016/j.bmcl.2009.02.079

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of hepatitis C virus (HCV) NS3/4A protease inhibitors bearing a P2-P4 macrocycle and a P1-P1' alpha-ketoamide serine trap is reported. The NS3 protease, which is essential for viral replication, is considered one of the most attractive targets for developing novel anti-HCV therapies. The optimization of both the macrocycle and the warhead portions led to the discovery of compounds 8b and 8g with a good activity both in the enzyme as well as in the cell based (replicon) assays with favorable PK profile in a preclinical species. (c) 2009 Elsevier Ltd. All rights reserved.

引用

收藏

页码：2295 / 2298

页数：4

相关论文

共 30 条

[1] DMSO-aided o-iodoxybenzoic acid (IBX) oxidation of Fmoc-protected amino alcohols [J].

Chen, Jack J. ;

Aduda, Vince .

SYNTHETIC COMMUNICATIONS, 2007, 37 (19-21) :3493-3499

[2] P1 and P1′ optimization of [3,4]-bicycloproline P2 incorporated tetrapeptidyl α-ketoamide based HCV protease inhibitors [J].

Chen, SH ;

Lamar, J ;

Yip, Y ;

Victor, F ;

Johnson, RB ;

Wang, QM ;

Glass, JI ;

Heinz, B ;

Colacino, J ;

Guo, DQ ;

Tebbe, M ;

Munroe, JE .

LETTERS IN DRUG DESIGN & DISCOVERY, 2005, 2 (02) :118-123

[3] Simple preparation of polymer supported IBX esters and amides and their oxidative properties [J].

Chung, WJ ;

Kim, DK ;

Lee, YS .

TETRAHEDRON LETTERS, 2003, 44 (52) :9251-9254

[4] Evolution, synthesis and SAR of tripeptide α-ketoacid inhibitors of the hepatitis C virus NS3/NS4A serine protease [J].

Colarusso, S ;

Gerlach, B ;

Koch, U ;

Muraglia, E ;

Conte, I ;

Stansfield, I ;

Matassa, VG ;

Narjes, F .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (04) :705-708

[5] The design of drugs for HIV and HCV [J].

De Clercq, Erik .

NATURE REVIEWS DRUG DISCOVERY, 2007, 6 (12) :1001-1018

[6] Advances in the development of new therapeutic agents targeting the NS34A serine protease or the NS5B RNA-dependent RNA polymerase of the hepatitis C virus [J].

De Francesco, Raffaele ;

Carfi, Andrea .

ADVANCED DRUG DELIVERY REVIEWS, 2007, 59 (12) :1242-1262

[7] A versatile and highly selective hypervalent iodine (III)/2,2,6,6-tetramethyl-1-piperidinyloxyl-mediated oxidation of alcohols to carbonyl compounds [J].

DeMico, A ;

Margarita, R ;

Parlanti, L ;

Vescovi, A ;

Piancatelli, G .

JOURNAL OF ORGANIC CHEMISTRY, 1997, 62 (20) :6974-6977

[8] A USEFUL 12-I-5 TRIACETOXYPERIODINANE (THE DESS-MARTIN PERIODINANE) FOR THE SELECTIVE OXIDATION OF PRIMARY OR SECONDARY ALCOHOLS AND A VARIETY OF RELATED 12-I-5 SPECIES [J].

DESS, DB ;

MARTIN, JC .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1991, 113 (19) :7277-7287

[9] BOTH NS3 AND NS4A ARE REQUIRED FOR PROTEOLYTIC PROCESSING OF HEPATITIS-C VIRUS NONSTRUCTURAL PROTEINS [J].

FAILLA, C ;

TOMEI, L ;

DEFRANCESCO, R .

JOURNAL OF VIROLOGY, 1994, 68 (06) :3753-3760

[10]

FATIADI AJ, 1976, SYNTHESIS-STUTTGART, P65