Highly water-soluble matrix metalloproteinases inhibitors and their effects in a rat adjuvant-induced arthritis model
Highly water-soluble matrix metalloproteinases inhibitors and their effects in a rat adjuvant-induced arthritis model
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DOI：
10.1016/s0968-0896(02)00109-8
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发表时间：
2002-08-01
影响因子：
3.5
通讯作者：
Morikawa, T
中科院分区：
文献类型：
--
作者：
Fujisawa, T;Igeta, K;Morikawa, T
一系列新的基于琥珀酸酯的抗基质金属蛋白酶（MMPs）和肿瘤坏死因子（TNF）的双重抑制剂。设计、合成了具有高水溶性的转化酶（TACE），并对其抑制作用进行了评价。在P-2'位上的酸性或碱性官能团的取代提供了足够的水溶性，而没有显著的抑制效力损失。与具有酸性官能团的化合物（18 a和18 b）相比，在P-2'位具有胍基作为碱性官能团的化合物18 e在皮下给药后在大鼠血浆中表现出对靶酶的较长时间的广泛抑制（β 1（1/2）：2.0小时）。因此，代表性化合物18 e与化合物18 b一起。在大鼠关节炎模型（一种慢性软骨破坏模型）中评价了Marimastat和Trocade。由此得出结论，新合成的高度水溶性化合物18 e在最短的给药时间（3-7天）内显示出显著的抑制后爪肿胀和骨破坏的活性。(C)2002爱思唯尔科技有限公司。保留所有权利。
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.