Substituted tetracyclic indole core derivatives of HCV NS5A inhibitor MK-8742

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• 作者：Wensheng Yu^a ; ^{wensheng.yu@merck.com" class="auth_mail" title="E-mail the corresponding author} ; Guowei Zhou^a ; Craig A. Coburn^b ; Qingbei Zeng^a ; Ling Tong^a ; Michael P. Dwyer^a ; Bin Hu^c ; Bin Zhong^c ; Jinglai Hao^c ; Tao Ji^c ; Shuai Zan^c ; Lei Chen^a ; Robert Mazzola^a ; Jae-Hun Kim^a ; Deyou Sha^a ; Oleg Selyutin^a ; Stuart B. Rosenblum^a ; Brian Lavey^a ; Anilkumar G. Nair^a ; Seong Heon Kim^a ; Kerry M. Keertikar^a ; Laura Rokosz^d ; Sony Agrawal^d ; Rong Liu^e ; Ellen Xia^d ; Ying Zhai^d ; Stephanie Curry^e ; Patricia McMonagle^e ; Paul Ingravallo^e ; Ernest Asante-Appiah^e ; Shiying Chen^f ; Joseph A. Kozlowski^a
• 关键词：BVAZQCUMNICBAQ-PZHYSIFUSA-N ; WPYAXRMKAPEASP-ZPGYEBBTSA-N ; YMRDJTQTNBXZGH-GKQJGOKYSA-N ; DAGKKAIYGHXLJT-VPYCOWAPSA-N ; YRKMHJVTILGOJX-MZGVRTMSSA-N ; QEKPBCIKIXADMU-VPYCOWAPSA-N ; ZXSYHNKPSRDAKS-BWNUEVLRSA-N ; MGZRWHFXUDRFCO-QSGJOOOQSA-N ; CCBTWTUTQJQYAP-MDIMQYHWSA-N ; CXEUJQYRHKVALU-BWNUEVLRSA-N ; ASJIYJLUIXXRDT-YPAJRNDMSA-N ; FHKWEFCGXGKRRO-IUWVPRLVSA-N ; SKANXUXNUVIGRG-MLDJBCBCSA-N ; QSBJQEQIXVJUSO-YAOZGEIESA-N ; QPECVEJVBIYGQI-BYOVBNPPSA-N ; KQKDEZDBTFWHOF-HTTMSSTRSA-N ; ZOEGLCAJQWSXCA-WDRXDVLQSA-N ; LWIDDBD
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 October 2016
• 年：2016
• 卷：26
• 期：19
• 页码：4851-4856
• 全文大小：1073 K

文摘

As part of an ongoing effort in NS5A inhibition at Merck we now describe our efforts for introducing substitution around the tetracyclic indole core of MK-8742. Fluoro substitution on the core combined with the fluoro substitutions on the proline ring improved the potency against GT1a Y93H significantly. However, no improvement on GT2b potency was achieved. Limiting the fluoro substitution to C-1 of the tetracyclic indole core had a positive impact on the potency against the resistance associated variants, such as GT1a Y93H and GT2b, and the PK profile as well. Compounds, such as 62, with reduced potency shifts between wild type GT1a to GT2b, GT1a Y93H, and GT1a L31V were identified.