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

被引：23

作者：

Chen, SH ^{[1
]}

Lamar, J ^{[1
]}

Yip, Y ^{[1
]}

Victor, F ^{[1
]}

Johnson, RB ^{[1
]}

Wang, QM ^{[1
]}

Glass, JI ^{[1
]}

Heinz, B ^{[1
]}

Colacino, J ^{[1
]}

Guo, DQ ^{[1
]}

Tebbe, M ^{[1
]}

Munroe, JE ^{[1
]}

机构：

[1] Lilly Corp Ctr, Lilly Res Lab, Indianapolis, IN 46285 USA

来源：

LETTERS IN DRUG DESIGN & DISCOVERY | 2005年 / 2卷 / 02期

关键词：

HCV infection; NS3; protease; enzyme inhibition; replicon assay; cytotoxicity; alpha-ketoamide;

D O I：

10.2174/1570180053175115

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We describe herein tetrapeptidyl alpha-ketoamide 4A based systematic P1 modifications alone or/and in combination with further P1' variations. These SAR efforts led to the discovery of a number of potent and selective HCV NS3 protease inhibitors such as 4B, 9, and 12 endowed with impressive cellular activity as measured in the replicon assay and very good therapeutic indexes. On the basis of its overall profile, compound 4B (VX-950) has been selected for human clinical trials.

引用

页码：118 / 123

页数：6

共 33 条

[1] The design and synthesis of potent inhibitors of hepatitis C virus NS3-4A proteinase [J].

Attwood, MR ;

Bennett, JM ;

Campbell, AD ;

Canning, GGM ;

Carr, MG ;

Conway, E ;

Dunsdon, RM ;

Greening, JR ;

Jones, PS ;

Kay, PB ;

Handa, BK ;

Hurst, DN ;

Jennings, NS ;

Jordan, S ;

Keech, E ;

O'Brien, MA ;

Overton, HH ;

King-Underwood, J ;

Raynham, TM ;

Stenson, KP ;

Wilkinson, CS ;

Wilkinson, TCI ;

Wilson, FX .

ANTIVIRAL CHEMISTRY & CHEMOTHERAPY, 1999, 10 (05) :259-273

[2] Molecular targets in inhibition of hepatitis C virus replication [J].

Bartenschlager, R .

ANTIVIRAL CHEMISTRY & CHEMOTHERAPY, 1997, 8 (04) :281-301

[3] Efficient initiation of HCV RNA replication in cell culture [J].

Blight, KJ ;

Kolykhalov, AA ;

Rice, CM .

SCIENCE, 2000, 290 (5498) :1972-1974

[4] The diisopropylcarbodiimide/1-hydroxy-7-azabenzotriazole system: Segment coupling and stepwise peptide assembly [J].

Carpino, LA ;

El-Faham, A .

TETRAHEDRON, 1999, 55 (22) :6813-6830

[5] PYBOP - A NEW PEPTIDE COUPLING REAGENT DEVOID OF TOXIC BY-PRODUCT [J].

COSTE, J ;

LENGUYEN, D ;

CASTRO, B .

TETRAHEDRON LETTERS, 1990, 31 (02) :205-208

[6] READILY ACCESSIBLE 12-I-5 OXIDANT FOR THE CONVERSION OF PRIMARY AND SECONDARY ALCOHOLS TO ALDEHYDES AND KETONES [J].

DESS, DB ;

MARTIN, JC .

JOURNAL OF ORGANIC CHEMISTRY, 1983, 48 (22) :4155-4156

[7]

Dymock B W, 2001, Expert Opin Emerg Drugs, V6, P13, DOI 10.1517/14728214.6.1.13

[8]

ELI LILLY, 2003, Patent No. 0218369

[9] Glycine α-ketoamides as HCVNS3 protease inhibitors [J].

Han, W ;

Hu, ZL ;

Jiang, XJ ;

Wasserman, ZR ;

Decicco, CP .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (06) :1111-1114

[10] Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis [J].

Heathcote, EJ ;

Shiffman, ML ;

Cooksley, WGE ;

Dusheiko, GM ;

Lee, SS ;

Balart, L ;

Reindollar, R ;

Reddy, RK ;

Wright, TL ;

Lin, A ;

Hoffman, J ;

De Pamphilis, J .

NEW ENGLAND JOURNAL OF MEDICINE, 2000, 343 (23) :1673-1680

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