Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 2: Discovery of potent, selective, and orally bioavailable compounds

被引：32
|
作者：
Shen, DM
Shu, M
Willoughby, CA
Shah, S
Lynch, CL
Hale, JJ
Mills, SG
Chapman, KT
Malkowitz, L
Springer, MS
Gould, SL
DeMartino, JA
Siciliano, SJ
Lyons, K
Pivnichny, JV
Kwei, GY
Carella, A
Carver, G
Holmes, K
Schleif, WA
Danzeisen, R
Hazuda, D
Kessler, J
Lineberger, J
Miller, MD
Emini, EA
机构：
[1] Merck Res Labs, Dept Med Chem, Rahway, NJ 07065 USA
[2] Merck Res Labs, Dept Immunol, Rahway, NJ 07065 USA
[3] Merck Res Labs, Dept Drug Metab, Rahway, NJ 07065 USA
[4] Merck Res Labs, Dept Antiviral Res, W Point, PA 19486 USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2004年 / 14卷 / 04期
关键词：
CCR5; antagonist; HIV-1; antiviral; pyrazole;
D O I：
10.1016/j.bmcl.2003.12.005
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Modifications of the alkyl acetic acid portion and the phenyl on pyrrolidine in our lead pyrazole compound I afforded the isopropyl compound 9. This compound is a potent CCR5 antagonist showing good in vitro antiviral activity against HIV-1, an excellent selectivity profile, and good oral bioavailability in three animal species. During this investigation, a new method for the preparation of alpha-(pyrrolidin-1-yl)-alpha,alpha-dialkyl acetic acid from a pyrrolidine and alpha-bromo-alpha,alpha-dialkyl acetic acid using silver triflate was discovered. This allowed us to prepare compounds such as 24 and 25 for the first time. A novel Pd-mediated N-dealkylation of alpha-(pyrrolidin-1-yl)acetic acid was also uncovered. (C) 2004 Elsevier Ltd. All rights reserved.
引用
收藏
页码：941 / 945
页数：5
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