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

作者：Iou‐Jiun Kang, Sheng-Ju Hsu, Huiyun 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 · 发表于：Journal of Medicinal Chemistry · 年份：2016 · DOI：10.1021/acs.jmedchem.6b00962 · 被引用次数：23 · 研究领域：Hepatitis C virus research、HIV/AIDS drug development and treatment、Quinazolinone synthesis and applications

Starting from the initial lead 4-phenylthiazole 18, a modest HCV inhibitor (EC 50 = 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 (EC 50 = 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 (EC 50 = 4.6 nM), with greater therapeutic index (CC 50 /EC 50 > 10000). Pharmacokinetic studies revealed that compound 57 had a superior oral exposure and desired bioavailability of 45% after oral administration in rats.