Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor
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- 作者：Steven Harper ; John A. McCauley ; Michael T. Rudd ; Marco Ferrara ; Marcello DiFilippo ; Benedetta Crescenzi ; Uwe Koch ; Alessia Petrocchi ; M. Katharine Holloway ; John W. Butcher ; Joseph J. Romano ; Kimberly J. Bush ; Kevin F. Gilbert ; Charles J. McIntyre ; Kevin T. Nguyen ; Emanuela Nizi ; Steven S. Carroll ; Steven W. Ludmerer ; Christine Burlein ; Jillian M. DiMuzio ; Donald J. Graham ; Carolyn M. McHale ; Mark W. Stahlhut ; David B. Olsen ; Edith Monteagudo ; Simona Cianetti ; Claudio Giuliano ; Vincenzo Pucci ; Nicole Trainor ; Christine M. Fandozzi ; Michael Rowley ; Paul J. Coleman ; Joseph P. Vacca ; Vincenzo Summa ; Nigel J. Liverton
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：April 12, 2012
- 年：2012
- 卷：3
- 期：4
- 页码：332-336
- 全文大小：293K
- 年卷期：v.3,no.4(April 12, 2012)
- ISSN：1948-5875
文摘
A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1鈥? NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.