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.
Journal of medicinal chemistry. 2015 Dec 27 [Epub ahead of print]
Scott D Edmondson, Cheng Zhu, Nam Fung Kar, Jerry Di Salvo, Hiroshi Nagabukuro, Beatrice Sacre-Salem, Karen Dingley, Richard Berger, Stephen Goble, Gregori Joseph Morriello, Bart Harper, Christopher R Moyes, Dong-Ming Shen, Liping Wang, Richard G Ball, Aileen Fitzmaurice, Tara Frenkl, Louise Gichuru, Sookhee Nicole Ha, Amanda Hurley, Nina Jochnowitz, Dorothy Levorse, Sruty Mistry, Randy Miller, James Ormes, Gino Salituro, Anthony Sanfiz, Andra Stevenson, Katherine Villa, Beata Zamlynny, Stuart Green, Mary Struthers, Ann E Weber