Potent Nonimmunosuppressive Cyclophilin Inhibitors With Improved Pharmaceutical Properties and Decreased Transporter Inhibition

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• 作者：Jiping Fu ; Meiliana Tjandra ; Christopher Becker ; Dallas Bednarczyk ; Michael Capparelli ; Robert Elling ; Imad Hanna ; Roger Fujimoto ; Markus Furegati ; Subramanian Karur ; Theresa Kasprzyk ; Mark Knapp ; Kwan Leung ; Xiaolin Li ; Peichao Lu ; Wosenu Mergo ; Charlotte Miault ; Simon Ng ; David Parker ; Yunshan Peng ; Silvio Roggo ; Alexey Rivkin ; Robert L. Simmons ; Michael Wang ; Brigitte Wiedmann ; Andrew H. Weiss ; Linda Xiao ; Lili Xie ; Wenjian Xu ; Aregahegn Yifru ; Shengtian Yang ; Bo Zhou ; Zachary K. Sweeney
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：October 23, 2014
• 年：2014
• 卷：57
• 期：20
• 页码：8503-8516
• 全文大小：507K
• ISSN：1520-4804

文摘

Nonimmunosuppressive cyclophilin inhibitors have demonstrated efficacy for the treatment of hepatitis C infection (HCV). However, alisporivir, cyclosporin A, and most other cyclosporins are potent inhibitors of OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction of the side chain hydrophobicity of the P4 residue preserves cyclophilin binding and antiviral potency while decreasing transporter inhibition. Representative inhibitor 33 (NIM258) is a less potent transporter inhibitor relative to previously described cyclosporins, retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic profile in rats and dogs. An X-ray structure of 33 bound to rat cyclophilin D is reported.