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SCH 900188的发现：一种有效的丙型肝炎病毒NS5B聚合酶抑制剂前药作为开发候选药物。

Discovery of SCH 900188: A Potent Hepatitis C Virus NS5B Polymerase Inhibitor Prodrug As a Development Candidate.

作者信息

Chen Kevin X, Venkatraman Srikanth, Anilkumar Gopinadhan N, Zeng Qingbei, Lesburg Charles A, Vibulbhan Bancha, Velazquez Francisco, Chan Tin-Yau, Bennet Frank, Jiang Yueheng, Pinto Patrick, Huang Yuhua, Selyutin Oleg, Agrawal Sony, Huang Hsueh-Cheng, Li Cheng, Cheng Kuo-Chi, Shih Neng-Yang, Kozlowski Joseph A, Rosenblum Stuart B, Njoroge F George

机构信息

Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.

出版信息

ACS Med Chem Lett. 2013 Aug 12;5(3):244-8. doi: 10.1021/ml400192w. eCollection 2014 Mar 13.

DOI:10.1021/ml400192w
PMID:24900812
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4027611/
Abstract

Starting from indole-based hepatitis C virus (HCV) NS5B polymerase inhibitor lead compound 1, structure modifications were performed at multiple indole substituents to improve potency and pharmacokinetic (PK) properties. Bicyclic quinazolinone was found to be the best substituent at indole nitrogen, while 4,5-furanylindole was identified as the best core. Compound 11 demonstrated excellent potency. Its C2 N,N-dimethylaminoethyl ester prodrug 12 (SCH 900188) demonstrated significant improvement in PK and was selected as the development candidate.

摘要

从基于吲哚的丙型肝炎病毒（HCV）NS5B聚合酶抑制剂先导化合物1开始，在多个吲哚取代基上进行结构修饰以提高活性和药代动力学（PK）性质。发现双环喹唑啉酮是吲哚氮上的最佳取代基，而4,5-呋喃基吲哚被确定为最佳核心。化合物11表现出优异的活性。其C2 N,N-二甲基氨基乙酯前药12（SCH 900188）在药代动力学方面有显著改善，并被选为开发候选药物。

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