1,2-二芳基咪唑类化合物作为强效、环氧合酶-2选择性及口服活性抗炎药

1,2-Diarylimidazoles as potent, cyclooxygenase-2 selective, and orally active antiinflammatory agents.

作者信息

Khanna I K, Weier R M, Yu Y, Xu X D, Koszyk F J, Collins P W, Koboldt C M, Veenhuizen A W, Perkins W E, Casler J J, Masferrer J L, Zhang Y Y, Gregory S A, Seibert K, Isakson P C

机构信息

Searle Research and Development, Skokie, Illinois 60077, USA.

出版信息

J Med Chem. 1997 May 23;40(11):1634-47. doi: 10.1021/jm9700225.

DOI:10.1021/jm9700225

PMID:9171873

Abstract

Series of 1,2-diarylimidazoles has been synthesized and found to contain highly potent and selective inhibitors of the human COX-2 enzyme. The paper describes a short synthesis of the target 1,2-diarylimidazoles starting with aryl nitriles. Different portions of the diarylimidazole (I) were modified to establish SAR. Systematic variations of the substituents in the aryl ring B have yielded very potent (IC50 = 10-100 nm) and selective (1000-12500) inhibitors of the COX-2 enzyme. The study on the influence of substituents in the imidazole ring established that a CF3 group at position 4 gives the optimum oral activity. A number of the diarylimidazoles showed excellent inhibition in the adjuvant induced arthritis model (e.g., ED50 = 0.02 mpk for 22 and 34). The diarylimidazoles are also potent inhibitors of carrageenan-induced edema (ED50 = 9-30 mpk) and hyperalgesia (ED50 = 11-40 mpk). Several orally active diarylimidazoles show no GI toxicity in the rat and mouse up to 200 mpk.

摘要

已合成了一系列1,2 - 二芳基咪唑，并发现其中含有对人COX - 2酶具有高效和选择性的抑制剂。本文描述了一种以芳基腈为起始原料的目标1,2 - 二芳基咪唑的简短合成方法。对二芳基咪唑（I）的不同部分进行修饰以确定构效关系。芳环B中取代基的系统变化产生了对COX - 2酶非常有效的（IC50 = 10 - 100纳米）和选择性的（1000 - 12500）抑制剂。对咪唑环中取代基影响的研究表明，4位的CF3基团具有最佳的口服活性。许多二芳基咪唑在佐剂诱导的关节炎模型中表现出优异的抑制作用（例如，化合物22和34的ED50 = 0.02毫克/千克）。二芳基咪唑也是角叉菜胶诱导的水肿（ED50 = 9 - 30毫克/千克）和痛觉过敏（ED50 = 11 - 40毫克/千克）的有效抑制剂。几种口服活性二芳基咪唑在大鼠和小鼠中高达200毫克/千克时均未表现出胃肠道毒性。