与SC-41930相关的第二代白三烯B4（LTB4）受体拮抗剂的设计与合成

The design and synthesis of second generation leukotriene B4 (LTB4) receptor antagonists related to SC-41930.

作者信息

Penning T D, Djuric S W, Docter S H, Yu S S, Spangler D, Anglin C P, Fretland D J, Kachur J F, Keith R H, Tsai B S

机构信息

Department of Chemistry, Searle Research and Development, Skokie, IL 60077.

出版信息

Agents Actions. 1993;39 Spec No:C11-3. doi: 10.1007/BF01972705.

DOI:10.1007/BF01972705

PMID:8273545

Abstract

SC-41930, 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4- dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid, is a selective, orally active, LTB4 receptor antagonist currently in clinical trials for psoriasis and ulcerative colitis. Exhaustive SAR studies found a potential backup compound, SC-50605, which was 7-16 times more potent than SC-41930 in LTB4 receptor binding, chemotaxis and degranulation assays. SC-50605 also inhibited LTB4-induced intradermal chemotaxis in cavine skin at an oral dose of 0.10 mg/kg and displayed good activity in animal models of colitis and epidermal inflammation both orally and topically.

摘要

SC - 41930，即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，是一种选择性、口服活性的白三烯B4（LTB4）受体拮抗剂，目前正处于银屑病和溃疡性结肠炎的临床试验阶段。详尽的构效关系（SAR）研究发现了一种潜在的备用化合物SC - 50605，在LTB4受体结合、趋化性和脱颗粒试验中，其效力比SC - 41930强7至16倍。SC - 50605在口服剂量为0.10 mg/kg时，也能抑制LTB4诱导的豚鼠皮肤皮内趋化性，并且在结肠炎和表皮炎症的动物模型中，口服和局部给药均显示出良好的活性。