Azetidines and spiro azetidines as novel P2 units in hepatitis C virus NS3 protease inhibitors

• Type of Material: Article
• Authors: Lavanya Bondada, Emory University; Ramu Rondla, Emory University; Ugo Pradere, Emory University; Peng Liu, Emory University; Chengwei Li, Emory University; Drew Bobeck, RFS Pharma LLC; Tamara McBrayer, RFS Pharma LLC; Philip Tharnish, RFS Pharma LLC; Jerome Courcambeck, Genoscience-Pharma; Philippe Halfon, Genoscience-Pharma; Tony Whitaker, RFS Pharma LLC; Franck Amblard, Emory University; Steven Coats, Emory University; Raymond Schinazi, Emory University
• Language: English
• Date: 2013-12-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 Elsevier Ltd. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bmcl.2013.09.068
• Title of Journal or Parent Work: Bioorganic and Medicinal Chemistry Letters
• ISSN: 0960-894X
• Volume: 23
• Issue: 23
• Start Page: 6325
• End Page: 6330
• Grant/Funding Information: This work was supported in part by NIH grant 5P30-AI-50409 (CFAR), and by the Department of Veterans Affairs.
• Keywords: Protease inhibitor; Science & Technology; HCV; Pharmacology & Pharmacy; REPLICATION; ACID; Chemistry; Chemistry, Organic; Antiviral; Physical Sciences; Life Sciences & Biomedicine; Chemistry, Medicinal
• Research Categories: Chemistry, Biochemistry; Biology, Virology

Abstract

Herein, we report the synthesis and structure-activity relationship studies of new analogs of boceprevir 1 and telaprevir 2. Introduction of azetidine and spiroazetidines as a P2 substituent that replaced the pyrrolidine moiety of 1 and 2 led to the discovery of a potent hepatitis C protease inhibitor 37c (EC50= 0.8 μM).