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

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journal contribution
posted on 28.01.2016, 00:00 by Scott D. Edmondson, Cheng Zhu, Nam Fung Kar, Jerry Di Salvo, Hiroshi Nagabukuro, Beatrice Sacre-Salem, Karen Dingley, Richard Berger, Stephen D. Goble, Gregori Morriello, Bart Harper, Christopher R. Moyes, Dong-Ming Shen, Liping Wang, Richard Ball, Aileen Fitzmaurice, Tara Frenkl, Loise N. Gichuru, Sookhee Ha, Amanda L. Hurley, Nina Jochnowitz, Dorothy Levorse, Shruty Mistry, Randy R. Miller, James Ormes, Gino M. Salituro, Anthony Sanfiz, Andra S. Stevenson, Katherine Villa, Beata Zamlynny, Stuart Green, Mary Struthers, Ann E. Weber
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.