Naito Y, Goto T, Akahoshi F, Ono S, Yoshitomi H, Okano T, Sugiyama N, Abe S, Hanada S, Hirata M
Central Research Laboratories, Green Cross Corporation, Osaka, Japan.
Chem Pharm Bull (Tokyo). 1991 Sep;39(9):2323-32. doi: 10.1248/cpb.39.2323.
A series of 2-[4-(thiazol-2-yl)phenyl]propionic acids substituted at various positions were prepared by the reaction of diethyl 2-methyl-2-(4-thiocarbamoylphenyl)malonates with alpha-bromoaldehyde diethyl acetals or alpha-haloketones followed by hydrolysis of esters. The inhibition of prostaglandin H synthetase (cyclooxygenase) was assayed by use of an enzyme preparation from guinea pig polymorphonuclear leukocytes. Examination of the structure-activity relationship of these compounds indicated that the substitution pattern with halogens at position 3 (R1) of the benzene ring and a methyl group in position 4 (R2) and/or 5 (R3) of the thiazole ring were favorable for inhibitory activity. The compounds bearing bulky alkyl or polar functional groups at the R2 position were weak inhibitors. The potent inhibitors of cyclooxygenase were tested for their ability to reduce carrageenin-induced inflammation of rat paws. These derivatives had strong anti-inflammatory activity based on their strong inhibition of cyclooxygenase, with some exceptions, including those with a thiomethyl group at R1.
通过2-甲基-2-(4-硫代氨基甲酰基苯基)丙二酸二乙酯与α-溴代醛二乙缩醛或α-卤代酮反应，随后进行酯水解，制备了一系列在不同位置被取代的2-[4-(噻唑-2-基)苯基]丙酸。使用豚鼠多形核白细胞的酶制剂测定前列腺素H合成酶（环氧化酶）的抑制作用。对这些化合物的构效关系研究表明，苯环3位（R1）上的卤素取代模式以及噻唑环4位（R2）和/或5位（R3）上的甲基有利于抑制活性。在R2位置带有庞大烷基或极性官能团的化合物是弱抑制剂。测试了环氧化酶的强效抑制剂减轻角叉菜胶诱导的大鼠爪炎症的能力。基于它们对环氧化酶的强烈抑制作用，这些衍生物具有很强的抗炎活性，但有一些例外，包括R1位带有硫甲基的那些化合物。
