학술논문
Structure–ActivityRelationship (SAR) Optimizationof 6-(Indol-2-yl)pyridine-3-sulfonamides: Identification ofPotent, Selective, and Orally Bioavailable Small Molecules TargetingHepatitis C (HCV) NS4B.
Document Type
Article
Author
Zhang, Nanjing; Zhang, Xiaoyan; Zhu, Jin; Turpoff, Anthony; Chen, Guangming; Morrill, Christie; Huang, Song; Lennox, William; Kakarla, Ramesh; Liu, Ronggang; Li, Chunshi; Ren, Hongyu; Almstead, Neil; Venkatraman, Srikanth; Njoroge, F. George; Gu, Zhengxian; Clausen, Valerie; Graci, Jason; Jung, Stephen P.; Zheng, Yingcong
Source
Subject
*HEPATITIS C
*STRUCTURE-activity relationship in pharmacology
*PYRIDINE
*VIRAL replication
*SMALL molecules
*TARGETED drug delivery
SULFONAMIDE drugs
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Language
ISSN
0022-2623
Abstract
A novel, potent, and orally bioavailableinhibitor of hepatitisC RNA replication targeting NS4B, compound 4t(PTC725),has been identified through chemical optimization of the 6-(indol-2-yl)pyridine-3-sulfonamide 2to improve DMPK and safety properties. The focus of theSAR investigations has been to identify the optimal combination ofsubstituents at the indole N-1, C-5, and C-6 positions and the sulfonamidegroup to limit the potential for in vivo oxidative metabolism andto achieve an acceptable pharmacokinetic profile. Compound 4thas excellent potency against the HCV 1b replicon, with an EC50= 2 nM and a selectivity index of >5000 with respecttocellular GAPDH. Compound 4thas an overall favorablepharmacokinetic profile with oral bioavailability values of 62%, 78%,and 18% in rats, dogs, and monkeys, respectively, as well as favorabletissue distribution properties with a liver to plasma exposure ratioof 25 in rats. [ABSTRACT FROM AUTHOR]