| Literature DB >> 26709102 |
Scott D Edmondson1, Cheng Zhu1, Nam Fung Kar1, Jerry Di Salvo1, Hiroshi Nagabukuro1, Beatrice Sacre-Salem1, Karen Dingley1, Richard Berger1, Stephen D Goble1, Gregori Morriello1, Bart Harper1, Christopher R Moyes1, Dong-Ming Shen1, Liping Wang1, Richard Ball1, Aileen Fitzmaurice1, Tara Frenkl1, Loise N Gichuru1, Sookhee Ha1, Amanda L Hurley1, Nina Jochnowitz1, Dorothy Levorse1, Shruty Mistry1, Randy R Miller1, James Ormes1, Gino M Salituro1, Anthony Sanfiz1, Andra S Stevenson1, Katherine Villa1, Beata Zamlynny1, Stuart Green1, Mary Struthers1, Ann E Weber1.
Abstract
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.Entities:
Mesh：
Substances：
Year: 2016 PMID： 26709102 DOI： 10.1021/acs.jmedchem.5b01372
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446