Penning T D, Chandrakumar N S, Chen B B, Chen H Y, Desai B N, Djuric S W, Docter S H, Gasiecki A F, Haack R A, Miyashiro J M, Russell M A, Yu S S, Corley D G, Durley R C, Kilpatrick B F, Parnas B L, Askonas L J, Gierse J K, Harding E I, Highkin M K, Kachur J F, Kim S H, Krivi G G, Villani-Price D, Pyla E Y, Smith W G
Departments of Medicinal Chemistry, Structure-Activity Screening Program, Inflammatory Diseases Research, and Molecular Pharmacology, Searle Research and Development, Monsanto Company, Skokie, Illinois 60077, USA.
J Med Chem. 2000 Feb 24;43(4):721-35. doi: 10.1021/jm990496z.
Leukotriene B(4) (LTB(4)) is a pro-inflammatory mediator that has been implicated in the pathogenesis of a number of diseases including inflammatory bowel disease (IBD) and psoriasis. Since the action of LTA(4) hydrolase is the rate-limiting step for LTB(4) production, this enzyme represents an attractive pharmacological target for the suppression of LTB(4) production. From an in-house screening program, SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) was identified as a potent inhibitor of LTA(4) hydrolase. Structure-activity relationship (SAR) studies around this structural class resulted in the identification of a number of novel, potent inhibitors of LTA(4) hydrolase, several of which demonstrated good oral activity in a mouse ex vivo whole blood assay.
白三烯B(4)（LTB(4)）是一种促炎介质，与包括炎症性肠病（IBD）和银屑病在内的多种疾病的发病机制有关。由于LTA(4)水解酶的作用是LTB(4)产生的限速步骤，因此该酶是抑制LTB(4)产生的一个有吸引力的药理学靶点。通过内部筛选程序，SC-22716（1, 1-[2-(4-苯氧基苯氧基)乙基]吡咯烷）被鉴定为LTA(4)水解酶的强效抑制剂。围绕这一结构类别的构效关系（SAR）研究导致鉴定出许多新型的、强效的LTA(4)水解酶抑制剂，其中几种在小鼠离体全血试验中表现出良好的口服活性。
