Discovery and Preclinical Characterization of the Cyclopropylindolobenzazepine BMS-791325, A Potent Allosteric Inhibitor of the Hepatitis C Virus NS5B Polymerase

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• 作者：Robert G. Gentles ; 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
• 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：1855-1879
• 全文大小：1060K
• 年卷期：v.57,no.5(March 13, 2014)
• ISSN：1520-4804

文摘

Described herein are structure鈥揳ctivity 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.