Discovery of Vaniprevir (MK-7009), a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor
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- 作者：John A. McCauley ; Charles J. McIntyre ; Michael T. Rudd ; Kevin T. Nguyen ; Joseph J. Romano ; John W. Butcher ; Kevin F. Gilbert ; Kimberly J. Bush ; M. Katharine Holloway ; John Swestock ; Bang-Lin Wan ; Stev
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：March 25, 2010
- 年：2010
- 卷：53
- 期：6
- 页码：2443-2463
- 全文大小：1243K
- 年卷期：v.53,no.6(March 25, 2010)
- ISSN：1520-4804
文摘
A new class of HCV NS3/4a protease inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the P2 to P4 linker, and the P1 side chain of this class of compounds via a modular synthetic strategy allowed for the optimization of enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 35b (vaniprevir, MK-7009), which is active against both the genotype 1 and genotype 2 NS3/4a protease enzymes and has good plasma exposure and excellent liver exposure in multiple species.