Highly water-soluble matrix metalloproteinases inhibitors and their effects in a rat adjuvant-induced arthritis model

被引：45

作者：

Fujisawa, T ^{[1
]}

Igeta, K ^{[1
]}

Odake, S ^{[1
]}

Morita, Y ^{[1
]}

Yasuda, J ^{[1
]}

Morikawa, T ^{[1
]}

机构：

[1] Daiichi Fine Chem Co Ltd, Inst Res, Takaoka, Toyama 9338511, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2002年 / 10卷 / 08期

关键词：

D O I：

10.1016/S0968-0896(02)00109-8

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 new series of succinate-based dual inhibitors against matrix metalloproteinases (MMPs) and tumor necrosis factor or. converting enzyme (TACE) possessing highly-water solubility was designed, synthesized, and evaluated for enzyme inhibition. Incorporating of acidic or basic functional groups at the P-2' position afforded sufficient water solubility without significant loss of inhibitory potencies. Compound 18e, which had a guanidino group at the P-2' position as the basic functional group, exhibited broad inhibition against target enzymes for a relatively long period in rat plasma (beta1(1/2): 2.0 h) after sc administration when compared with compounds possessing acidic functional groups (18a and 18b). Consequently, the representative compound 18e together with compound 18b. Marimastat and Trocade were evaluated in the rat adjuvant-induced arthritis model, a model of chronic cartilage destruction. It is concluded that the newly synthesized highly water-soluble compound 18e showed significant activity in suppressing hindpaw swelling and the bone destruction with a minimal administration period (days 3-7). (C) 2002 Elsevier Science Ltd. All rights reserved.

引用

页码：2569 / 2581

页数：13

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