Discovery of Vibegron: A Potent and Selective β3 Adrenergic Receptor Agonist for the Treatment of Overactive Bladder

被引：84

作者：

Edmondson, Scott D. ^{[1
]}

Zhu, Cheng ^{[1
]}

Kar, Nam Fung ^{[1
]}

Di Salvo, Jerry ^{[1
]}

Nagabukuro, Hiroshi ^{[1
]}

Sacre-Salem, Beatrice ^{[1
]}

Dingley, Karen ^{[1
]}

Berger, Richard ^{[1
]}

Goble, Stephen D. ^{[1
]}

Morriello, Gregori ^{[1
]}

Harper, Bart ^{[1
]}

Moyes, Christopher R. ^{[1
]}

Shen, Dong-Ming ^{[1
]}

Wang, Liping ^{[1
]}

Ball, Richard ^{[1
]}

Fitzmaurice, Aileen ^{[1
]}

Frenkl, Tara ^{[1
]}

Gichuru, Loise N. ^{[1
]}

Ha, Sookhee ^{[1
]}

Hurley, Amanda L. ^{[1
]}

Jochnowitz, Nina ^{[1
]}

Levorse, Dorothy ^{[1
]}

Mistry, Shruty ^{[1
]}

Miller, Randy R. ^{[1
]}

Ormes, James ^{[1
]}

Salituro, Gino M. ^{[1
]}

Sanfiz, Anthony ^{[1
]}

Stevenson, Andra S. ^{[1
]}

Villa, Katherine ^{[1
]}

Zamlynny, Beata ^{[1
]}

Green, Stuart ^{[1
]}

Struthers, Mary ^{[1
]}

Weber, Ann E. ^{[1
]}

机构：

[1] Merck Res Labs, 2015 Galloping Hill Rd,POB 539, Kenilworth, NJ 07033 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 02期

关键词：

LOWER URINARY-TRACT; HUMAN BETA(3)-ADRENERGIC RECEPTOR; C-FOS EXPRESSION; ENERGY-EXPENDITURE; DRUG CANDIDATES; RAT; INACTIVATION; TOLERABILITY; CONTRACTIONS; DISPOSITION;

D O I：

10.1021/acs.jmedchem.5b01372

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The discovery of vibegron, a potent and selective human beta(3)-AR agonist for the treatment of overactive bladder (OAB), is described. An early-generation clinical beta(3)-AR agonist MK-0634 (3) exhibited efficacy in humans for the treatment of OAB, but development was discontinued due to unacceptable structure-based toxicity in preclinical species. Optimization of a series of second-generation pyrrolidine-derived beta(3)-AR agonists included reducing the risk for phospholipidosis, the risk of formation of disproportionate human metabolites, and the risk of formation of high levels of circulating metabolites in preclinical species. These efforts resulted in the discovery of vibegron, which possesses improved druglike properties and an overall superior preclinical profile compared to MK-0634. Structure-activity relationships leading to the discovery of vibegron and a summary of its preclinical profile are described.

引用

页码：609 / 623

页数：15

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