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

页码：941 / 945

页数：5

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