A Potent, Selective, and Orally Bioavailable HCV NS5A Inhibitor for Treatment of Hepatitis C Virus: (S)-1-((R)-2-(Cyclopropanecarboxamido)-2-phenylacetyl)-N-(4-phenylthiazol-2-yl)pyrrolidine-2-carboxamide

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• 作者：Iou-Jiun Kang ; Sheng-Ju Hsu ; Hui-Yun Yang ; Teng-Kuang Yeh ; Chung-Chi Lee ; Yen-Chun Lee ; Ya-Wen Tian ; Jen-Shin Song ; Tsu-An Hsu ; Yu-Sheng Chao ; Andrew Yueh ; Jyh-Haur Chern
• 刊名：Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：January 12, 2017
• 年：2017
• 卷：60
• 期：1
• 页码：228-247
• 全文大小：787K
• ISSN：1520-4804

文摘

Starting from the initial lead 4-phenylthiazole 18, a modest HCV inhibitor (EC₅₀ = 9440 nM), a series of structurally related thiazole derivatives has been identified as a novel chemical class of potent and selective HCV NS5A inhibitors. The introduction of a carboxamide group between the thiazole and pyrrolidine ring (42) of compound 18 resulted in a dramatic increase in activity (EC₅₀ = 0.92 nM). However, 42 showed only moderate pharmacokinetic properties and limited oral bioavalability of 18.7% in rats. Further optimization of the substituents at the 4-position of the thiazole ring and pyrrolidine nitrogen of the lead compound 42 led to the identification of compound 57, a highly potent and selective NS5A inhibitor of HCV (EC₅₀ = 4.6 nM), with greater therapeutic index (CC₅₀/EC₅₀ > 10000). Pharmacokinetic studies revealed that compound 57 had a superior oral exposure and desired bioavailability of 45% after oral administration in rats.