An Imidazopiperidine Series of CCR5 Antagonists for the Treatment of HIV: The Discovery of N-{(1S)-1-(3-Fluorophenyl)-3-[(3-endo)-3-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H
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- 作者：Paul A. Stupple ; David V. Batchelor ; Martin Corless ; Patrick K. Dorr ; David Ellis ; David R. Fenwick ; S茅bastien R. G. Galan ; Rhys M. Jones ; Helen J. Mason ; Donald S. Middleton ; Manos Perros ; Francesca Perruccio ; Michelle Y. Platts ; David C. Pryde ; Deborah Rodrigues ; Nicholas N. Smith ; Peter T. Stephenson ; Robert Webster ; Mike Westby ; Anthony Wood
- 刊名：Journal of Medicinal Chemistry
- 出版年：2011
- 出版时间：January 13, 2011
- 年：2011
- 卷：54
- 期：1
- 页码：67-77
- 全文大小：989K
- 年卷期：v.54,no.1(January 13, 2011)
- ISSN：1520-4804
文摘
Preventing entry of HIV into human host cells has emerged as an attractive approach to controlling viral replication. Maraviroc 1 is an approved antagonist of the human CCR5 receptor which prevents the entry of HIV. Herein, we report the design and discovery of a series of imidazopiperidine CCR5 antagonists which retain the attractive antiviral profile and window over hERG activity of maraviroc 1, combined with improved absorption profiles in rat and dog. Furthermore, this series of compounds has been shown to retain activity against a laboratory generated maraviroc-resistant HIV-1 strain, which indicates an alternative resistance profile to that of maraviroc 1. Compound 41f (PF-232798) was selected as a clinical candidate from the imidazopiperidine series and is currently in phase II clinical trials.