Boyd S A, Mantei R A, Tasker A S, Liu G, Sorensen B K, Henry K J, von Geldern T W, Winn M, Wu-Wong J R, Chiou W J, Dixon D B, Hutchins C W, Marsh K C, Nguyen B, Opgenorth T J
Metabolic Disease Research, Abbott Laboratories, Pharmaceutical Products Division, Abbott Park, IL 60064-6101, USA.
Bioorg Med Chem. 1999 Jun;7(6):991-1002. doi: 10.1016/s0968-0896(99)00022-x.
Endothelins, ET-1, ET-2, and ET-3 are potent vasoconstricting and mitogenic 21-amino acid bicyclic peptides, which exert their effects upon binding to the ET(A) and ET(B) receptors. The ET(A) receptor mediates vasoconstriction and smooth muscle cell proliferation, and the ET(B) receptor mediates different effects in different tissues, including nitric oxide release from endothelial cells, and vasoconstriction in certain vascular cell types. Selective antagonists of endothelin receptor subtypes may prove useful in determining the role of endothelin in various tissue types and disease states, and hence as therapeutic agents for such diseases. The pyrrolidine carboxylic acid A-127722 has been disclosed as a potent and ET(A)-selective antagonist, and is currently undergoing clinical trials. In our efforts to find antagonists with altered selectivity (ET(A)-selective, ET(B)-selective, or nonselective), we investigated the SAR of the 2-substituent on the pyrrolidine. Compounds with alkyl groups at the 2-position possessed ET(A) selectivity improved over A-127722 (1400-fold selective), with the best of these compounds showing nearly 19,000-fold selectivity.
内皮素、ET-1、ET-2和ET-3是具有强大血管收缩作用和促有丝分裂作用的21个氨基酸的双环肽，它们通过与ET(A)和ET(B)受体结合发挥作用。ET(A)受体介导血管收缩和平滑肌细胞增殖，而ET(B)受体在不同组织中介导不同作用，包括内皮细胞释放一氧化氮以及某些血管细胞类型的血管收缩。内皮素受体亚型的选择性拮抗剂可能在确定内皮素在各种组织类型和疾病状态中的作用方面证明有用，因此可作为此类疾病的治疗药物。吡咯烷羧酸A-127722已被披露为一种强效且对ET(A)有选择性的拮抗剂，目前正在进行临床试验。在我们寻找具有改变选择性（ET(A)选择性、ET(B)选择性或非选择性）的拮抗剂的过程中，我们研究了吡咯烷上2-取代基的构效关系。在2-位带有烷基的化合物具有比A-127722更高的ET(A)选择性（选择性提高了1400倍），其中最好的这些化合物显示出近19000倍的选择性。
