| Literature DB >> 24397558 |
Robert G Gentles1, Min Ding, John A Bender, Carl P Bergstrom, Katharine Grant-Young, Piyasena Hewawasam, Thomas Hudyma, Scott Martin, Andrew Nickel, Alicia Regueiro-Ren, Yong Tu, Zhong Yang, Kap-Sun Yeung, Xiaofan Zheng, Sam Chao, Jung-Hui Sun, Brett R Beno, Daniel M Camac, Chong-Hwan Chang, Mian Gao, Paul E Morin, Steven Sheriff, Jeff Tredup, John Wan, Mark R Witmer, Dianlin Xie, Umesh Hanumegowda, Jay Knipe, Kathy Mosure, Kenneth S Santone, Dawn D Parker, Xiaoliang Zhuo, Julie Lemm, Mengping Liu, Lenore Pelosi, Karen Rigat, Stacey Voss, Yi Wang, Ying-Kai Wang, Richard J Colonno, Min Gao, Susan B Roberts, Qi Gao, Alicia Ng, Nicholas A Meanwell, John F Kadow.
Abstract
Described herein are structure-activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and membrane permeability were shown to have notably enhanced pharmacokinetic profiles. Additionally, a series of alkyl bridged piperazine carboxamides was identified as being of particular interest, and from which the compound BMS-791325 (2) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation.Entities:
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Year: 2014 PMID： 24397558 DOI： 10.1021/jm4016894
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446