Synthesis, biological evaluation, and pharmacokinetic study of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives as VLA-4 antagonists

被引：32

作者：

Chiba, J

Takayama, G

Takashi, T

Yokoyama, M

Atsushi Nakayama, A

Baldwin, JJ

McDonald, E

Moriarty, KJ

Sarko, CR

Saionz, KW

Swanson, R

Hussain, Z

Wong, A

Machinaga, N

机构：

[1] Daiichi Pharmaceut Co Ltd, Res Inst, Med Chem Res Lab, Edogawa Ku, Tokyo 1348630, Japan

[2] Daiichi Pharmaceut Co Ltd, Res Inst, New Prod Res Labs 3, Edogawa Ku, Tokyo 1348630, Japan

[3] Pharmacopeia Drug Discovery Inc, Princeton, NJ 08543 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2006年 / 14卷 / 08期

关键词：

VLA-4; integrin;

D O I：

10.1016/j.bmc.2005.11.058

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A series of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives were synthesized and evaluated for their activity as VLA-4 antagonists. Of 22 compounds synthesized, 19 compounds showed potent activity with low nanomolar IC50 values. In addition, the representative compounds 11o and 11p with a hydroxy group in the pyrrolidine ring showed moderate plasma clearance in rats (11o, 30 ml/min/kg and 11p, 21 ml/min/kg) and in dogs (11o, 12ml/min/kg and 11p 9ml/min/kg). (c) 2005 Elsevier Ltd. All rights reserved.

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收藏

页码：2725 / 2746

页数：22

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