Journal of medicinal chemistry · 2016
Discovery of Vibegron: A Potent and Selective β3 Adrenergic Receptor Agonist for the Treatment of Overactive Bladder.
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Edmondson Scott D, Zhu Cheng, Kar Nam Fung, Di Salvo Jerry, Nagabukuro Hiroshi, Sacre-Salem Beatrice, Dingley Karen, Berger Richard, Goble Stephen D, Morriello Gregori, Harper Bart, Moyes Christopher R, Shen Dong-Ming, Wang Liping, Ball Richard, Fitzmaurice Aileen, Frenkl Tara, Gichuru Loise N, Ha Sookhee, Hurley Amanda L, Jochnowitz Nina, Levorse Dorothy, Mistry Shruty, Miller Randy R, Ormes James, Salituro Gino M, Sanfiz Anthony, Stevenson Andra S, Villa Katherine, Zamlynny Beata, Green Stuart, Struthers Mary, Weber Ann E
Аннотация
The discovery of vibegron, a potent and selective human β3-AR agonist for the treatment of overactive bladder (OAB), is described. An early-generation clinical β3-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 β3-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.
Предметные рубрики MeSH
Adrenergic beta-3 Receptor AgonistsAnimalsCHO CellsCricetinaeCricetulusDrug DiscoveryFemaleHumansLipidosesMicrosomes, LiverModels, MolecularPyrimidinonesPyrrolidinesRatsRats, Sprague-DawleyReceptors, Adrenergic, betaSerotonin Plasma Membrane Transport ProteinsStructure-Activity RelationshipUrinary BladderUrinary Bladder, OveractiveUrinationX-Ray Diffraction