Discovery of Potent Cyclophilin Inhibitors Based on the Structural Simplification of Sanglifehrin A

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• 作者：Victoria A. Steadman ; Simon B. Pettit ; Karine G. Poullennec ; Linos Lazarides ; Andrew J. Keats ; David K. Dean ; Steven J. Stanway ; Carol A. Austin ; Jonathan A. Sanvoisin ; Gregory M. Watt ; Hans G. Fliri ; Albert C. Liclican ; Debi Jin ; Melanie H. Wong ; Stephanie A. Leavitt ; Yu-Jen Lee ; Yang Tian ; Christian R. Frey ; Todd C. Appleby ; Uli Schmitz ; Petr Jansa ; Richard L. MackmanBrian E. Schultz
• 刊名：Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：February 9, 2017
• 年：2017
• 卷：60
• 期：3
• 页码：1000-1017
• 全文大小：714K
• ISSN：1520-4804

文摘

Cyclophilin inhibition has been a target for the treatment of hepatitis C and other diseases, but the generation of potent, drug-like molecules through chemical synthesis has been challenging. In this study, a set of macrocyclic cyclophilin inhibitors was synthesized based on the core structure of the natural product sanglifehrin A. Initial compound optimization identified the valine-m-tyrosine-piperazic acid tripeptide (Val-m-Tyr-Pip) in the sanglifehrin core, stereocenters at C14 and C15, and the hydroxyl group of the m-tyrosine (m-Tyr) residue as key contributors to compound potency. Replacing the C18–C21 diene unit of sanglifehrin with a styryl group led to potent compounds that displayed a novel binding mode in which the styrene moiety engaged in a π-stacking interaction with Arg55 of cyclophilin A (Cyp A), and the m-Tyr residue was displaced into solvent. This observation allowed further simplifications of the scaffold to generate new lead compounds in the search for orally bioavailable cyclophilin inhibitors.