Penning T D, Djuric S W, Miyashiro J M, Yu S, Snyder J P, Spangler D, Anglin C P, Fretland D J, Kachur J F, Keith R H
Department of Chemistry, Searle Research and Development, Skokie, Illinois 60077.
J Med Chem. 1995 Mar 17;38(6):858-68. doi: 10.1021/jm00006a002.
Our previous reports have highlighted the first-generation leukotriene B4 (LTB4) receptor antagonist SC-41930 (7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]3,4- dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid) which has potent oral, topical, and intracolonic activity in various animal models of inflammation. Extensive structure-activity relationship studies, in which a series of heterocyclic replacements for the methyl ketone functional group of SC-41930 was explored, identified SC-50605 (7-[3-[2-(cyclopropylmethyl)-3-methoxy-4- (4-thiazolyl)phenoxy]propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2- carboxylic acid) as an optimized analog within a series of thiazoles. SC-50605 was found to be significantly more potent than SC-41930 in LTB4 receptor binding, chemotaxis, and degranulation assays. It also displayed very good activity in animal models of colitis and epidermal inflammation by oral, topical, intravenous, and intracolonic routes of administration. The resolved enantiomers of SC-50605 were obtained by chiral chromatography and both demonstrated good in vitro and in vivo activity. The (+)-isomer (SC-52798) is currently being evaluated as a potential clinical candidate for psoriasis and ulcerative colitis therapy.
我们之前的报告重点介绍了第一代白三烯B4（LTB4）受体拮抗剂SC - 41930（7 - [3 - (4 - 乙酰基 - 3 - 甲氧基 - 2 - 丙基苯氧基)丙氧基]-3,4 - 二氢 - 8 - 丙基 - 2H - 1 - 苯并吡喃 - 2 - 羧酸），它在多种炎症动物模型中具有有效的口服、局部和结肠内活性。通过广泛的构效关系研究，探索了一系列用于取代SC - 41930甲基酮官能团的杂环化合物，确定了SC - 50605（7 - [3 - [2 - (环丙基甲基)-3 - 甲氧基 - 4 - (4 - 噻唑基)苯氧基]丙氧基]-3,4 - 二氢 - 8 - 丙基 - 2H - 1 - 苯并吡喃 - 2 - 羧酸）为一系列噻唑类中的优化类似物。在LTB4受体结合、趋化性和脱颗粒试验中，发现SC - 50605比SC - 41930的活性显著更高。通过口服、局部、静脉和结肠内给药途径，它在结肠炎和表皮炎症动物模型中也表现出非常好的活性。通过手性色谱法获得了SC - 50605的拆分对映体，两者均显示出良好的体外和体内活性。(+)-异构体（SC - 52798）目前正在作为银屑病和溃疡性结肠炎治疗的潜在临床候选药物进行评估。
