Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket

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• 作者：Johan Gising ; Anna Karin Belfrage ; Hiba Alogheli ; Angelica Ehrenberg ; Eva 脜kerblom ; Richard Svensson ; Per Artursson ; Anders Karl茅n ; U. Helena Danielson ; Mats Larhed ; Anja Sandstr枚m
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 13, 2014
• 年：2014
• 卷：57
• 期：5
• 页码：1790-1801
• 全文大小：539K
• 年卷期：v.57,no.5(March 13, 2014)
• ISSN：1520-4804

文摘

Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1鈥?position. Structure鈥揳ctivity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R⁶ substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to K_i = 0.11 渭M were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R⁶ substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.