Cyclic HIV protease inhibitors:: Design and synthesis of orally bioavailable, pyrazole P2/P2′ cyclic ureas with improved potency

被引：68

作者：

Han, Q ^{[1
]}

Chang, CH ^{[1
]}

Li, RH ^{[1
]}

Ru, Y ^{[1
]}

Jadhav, PK ^{[1
]}

Lam, PYS ^{[1
]}

机构：

[1] Dupont Merck Pharmaceut Co, Expt Stn, Wilmington, DE 19880 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1998年 / 41卷 / 12期

关键词：

D O I：

10.1021/jm9704199

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Highly potent HIV-1 protease (HIVPR) inhibitors have been designed and synthesized by introducing bidentate hydrogen-bonding oxime and pyrazole groups at the mete-position of the phenyl ring on the P2/P2' substituents of cyclic ureas. Nonsymmetrical cyclic ureas incorporating 3(1H)-pyrazolylbenzyl as P2 and hydrophilic functionalities as P2' show potent protease inhibition and antiviral activities against HIV and have good oral bioavailabilities. The X-ray structure of HTVPR.10A complex confirms that the two pyrazole rings of 10A form bidentate hydrogen bonds with the side-chain oxygen (C=O) and backbone nitrogen (N-H) of Asp30/30' of HIVPR.

引用

页码：2019 / 2028

页数：10