N-酰基吡咯并喹诺酮类磷酸二酯酶-5抑制剂的构效关系

Structure-activity relationships of N-acyl pyrroloquinolone PDE-5 inhibitors.

作者信息

Lanter James C, Sui Zhihua, Macielag Mark J, Fiordeliso James J, Jiang Weiqin, Qiu Yuhong, Bhattacharjee Sheela, Kraft Patricia, John T Mathew, Haynes-Johnson Donna, Craig Elizabeth, Clancy Joanna

机构信息

Drug Discovery, Johnson and Johnson Pharmaceutical Research and Development LLC, 1000 Route 202 S, P.O. Box 300, Raritan, New Jersey 08869, USA.

出版信息

J Med Chem. 2004 Jan 29;47(3):656-62. doi: 10.1021/jm020521s.

DOI:10.1021/jm020521s

PMID:14736245

Abstract

The discovery of the potent and selective PDE-5 inhibitory activity of a pyrroloquinolone scaffold prompted us to explore the SAR of its acyl derivatives. During the course of these studies, three structural series were found with K(i) values for PDE-5 in the subnanomolar range. Systematic modification of one of these leads produced a compound with excellent selectivity for PDE-5 over other phosphodiesterases and oral bioavailability of 15% in male rats. This compound also displayed in vivo efficacy in an anesthetized canine model of erection when dosed intravenously.

摘要

吡咯并喹诺酮骨架具有强效且选择性的 PDE-5 抑制活性，这一发现促使我们探索其酰基衍生物的构效关系。在这些研究过程中，发现了三个结构系列，其对 PDE-5 的 K(i) 值处于亚纳摩尔范围内。对其中一个先导化合物进行系统修饰，得到了一种对 PDE-5 相对于其他磷酸二酯酶具有优异选择性且在雄性大鼠中口服生物利用度为 15% 的化合物。当静脉给药时，该化合物在麻醉犬勃起模型中也显示出体内疗效。