Structure鈥揂ctivity Relationship (SAR) Optimization of 6-(Indol-2-yl)pyridine-3-sulfonamides: Identification of Potent, Selective, and Orally Bioavailable Small Molecules Targeting Hepatitis C (HCV) NS

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• 作者：Nanjing Zhang ; Xiaoyan Zhang ; Jin Zhu ; Anthony Turpoff ; Guangming Chen ; Christie Morrill ; Song Huang ; William Lennox ; Ramesh Kakarla ; Ronggang Liu ; Chunshi Li ; Hongyu Ren ; Neil Almstead ; Srikanth Venkatraman ; F. George Njoroge ; Zhengxian Gu ; Valerie Clausen ; Jason Graci ; Stephen P. Jung ; Yingcong Zheng ; Joseph M. Colacino ; Fred Lahser ; Josephine Sheedy ; Anna Mollin ; Marla Weetall ; Amin Nomeir ; Gary M. Karp
• 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：2121-2135
• 全文大小：512K
• 年卷期：v.57,no.5(March 13, 2014)
• ISSN：1520-4804

文摘

A novel, potent, and orally bioavailable inhibitor of hepatitis C RNA replication targeting NS4B, compound 4t (PTC725), has been identified through chemical optimization of the 6-(indol-2-yl)pyridine-3-sulfonamide 2 to improve DMPK and safety properties. The focus of the SAR investigations has been to identify the optimal combination of substituents at the indole N-1, C-5, and C-6 positions and the sulfonamide group to limit the potential for in vivo oxidative metabolism and to achieve an acceptable pharmacokinetic profile. Compound 4t has excellent potency against the HCV 1b replicon, with an EC₅₀ = 2 nM and a selectivity index of >5000 with respect to cellular GAPDH. Compound 4t has an overall favorable pharmacokinetic profile with oral bioavailability values of 62%, 78%, and 18% in rats, dogs, and monkeys, respectively, as well as favorable tissue distribution properties with a liver to plasma exposure ratio of 25 in rats.