Hilfiker Mark A, Zhang Daohua, Dowdell Sarah E, Goodman Krista B, McAtee John J, Dodson Jason W, Viet Andrew Q, Wang Gren Z, Sehon Clark A, Behm David J, Wu Zining, Carballo Luz H, Douglas Stephen A, Neeb Michael J
Department of Medicinal Chemistry, Cardiovascular and Urogenital Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406, USA.
Bioorg Med Chem Lett. 2008 Aug 15;18(16):4470-3. doi: 10.1016/j.bmcl.2008.07.067. Epub 2008 Jul 20.
Aminomethylpiperazines, reported previously as being kappa-opioid receptor agonists, were identified as lead compounds in the development of selective urotensin receptor antagonists. Optimized substitution of the piperazine moiety has provided high affinity urotensin receptor antagonists with greater than 100-fold selectivity over the kappa-opioid receptor. Select compounds were found to inhibit urotensin-induced vasoconstriction in isolated rat aortic rings consistent with the hypothesis that an urotensin antagonist may be useful for the treatment of hypertension.
氨甲基哌嗪，先前报道为κ-阿片受体激动剂，在选择性尿紧张素受体拮抗剂的开发中被确定为先导化合物。哌嗪部分的优化取代提供了对κ-阿片受体具有大于100倍选择性的高亲和力尿紧张素受体拮抗剂。发现选择性化合物可抑制分离的大鼠主动脉环中尿紧张素诱导的血管收缩，这与尿紧张素拮抗剂可能对治疗高血压有用的假设一致。
