P1 and P1; Optimization of [3,4]-Bicycloproline P2 Incorporated Tetrapeptidyl α-Ketoamide Based HCV Protease Inhibitors

Shu-Hui Chen; Jason Lamar; Yvonne Yip; Frantz Victor; Robert B. Johnson; Q. M. Wang; John I. Glass; Beverly Heinz; Joseph Colacino; Deqi Guo; Mark Tebbe; John E. Munroe

doi:10.2174/1570180053175115

ISSN: 1570-1808
E-ISSN: 1875-628X

P1 and P1; Optimization of [3,4]-Bicycloproline P2 Incorporated Tetrapeptidyl α-Ketoamide Based HCV Protease Inhibitors
Authors: Shu-Hui Chen¹, Jason Lamar², Yvonne Yip³, Frantz Victor⁴, Robert B. Johnson⁵, Q. M. Wang⁶, John I. Glass⁷, Beverly Heinz⁸, Joseph Colacino⁹, Deqi Guo¹⁰, Mark Tebbe¹¹ and John E. Munroe¹²
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¹ Lilly Research Laboratory, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. ² Lilly Research Laboratory, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. ³ Lilly Research Laboratory, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. ⁴ Lilly Research Laboratory, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. ⁵ Lilly Research Laboratory, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. ⁶ Lilly Research Laboratory, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. ⁷ Lilly Research Laboratory, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. ⁸ Lilly Research Laboratory, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. ⁹ Lilly Research Laboratory, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. ¹⁰ Lilly Research Laboratory, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. ¹¹ Lilly Research Laboratory, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. ¹² Lilly Research Laboratory, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Source: Letters in Drug Design & Discovery, Volume 2, Issue 2, Mar 2005, p. 118 - 123
DOI: https://doi.org/10.2174/1570180053175115
- Available online: 01 Mar 2005

Abstract

We describe herein tetrapeptidyl α-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.

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2005-03-01

2025-06-20

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Article Type: Review Article

Keyword(s): alpha-ketoamide; cytotoxicity; enzyme inhibition; hcv infection; ns3 protease; replicon assay

P1 and P1; Optimization of [3,4]-Bicycloproline P2 Incorporated Tetrapeptidyl α-Ketoamide Based HCV Protease Inhibitors

Abstract

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