title: Discovery of Vibegron: A Potent and Selective β3 Adrenergic Receptor Agonist for the Treatment of Overactive Bladder.
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.
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Edmondson
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Nam Fung
authors.initials: NF
authors.lastname: Kar
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Jerry
authors.initials: J
authors.lastname: Di Salvo
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagabukuro
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Sacre-Salem
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Karen
authors.initials: K
authors.lastname: Dingley
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Berger
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Goble
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Gregori
authors.initials: G
authors.lastname: Morriello
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Bart
authors.initials: B
authors.lastname: Harper
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Moyes
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Dong-Ming
authors.initials: DM
authors.lastname: Shen
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Ball
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Aileen
authors.initials: A
authors.lastname: Fitzmaurice
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Tara
authors.initials: T
authors.lastname: Frenkl
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Loise N
authors.initials: LN
authors.lastname: Gichuru
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Sookhee
authors.initials: S
authors.lastname: Ha
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Hurley
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Nina
authors.initials: N
authors.lastname: Jochnowitz
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Levorse
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Shruty
authors.initials: S
authors.lastname: Mistry
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Randy R
authors.initials: RR
authors.lastname: Miller
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: James
authors.initials: J
authors.lastname: Ormes
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Gino M
authors.initials: GM
authors.lastname: Salituro
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Anthony
authors.initials: A
authors.lastname: Sanfiz
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Andra S
authors.initials: AS
authors.lastname: Stevenson
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Katherine
authors.initials: K
authors.lastname: Villa
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Beata
authors.initials: B
authors.lastname: Zamlynny
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Stuart
authors.initials: S
authors.lastname: Green
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Mary
authors.initials: M
authors.lastname: Struthers
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Weber
mesh_terms: D058667:Adrenergic beta-3 Receptor Agonists / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D055808:Drug Discovery; D005260:Female; D006801:Humans; D008064:Lipidoses / Q000139:chemically induced; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D011744:Pyrimidinones / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D011759:Pyrrolidines / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D001743:Urinary Bladder / Q000187:drug effects; D053201:Urinary Bladder, Overactive / Q000188:drug therapy*; D014554:Urination / Q000187:drug effects; D014961:X-Ray Diffraction
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; C000608232:N-(4-((5-(hydroxy(phenyl)methyl)pyrrolidin-2-yl)methyl)phenyl)-4-oxo-4,6,7,8-tetrahydropyrrolo(1,2-a)pyrimidine-6-carboxamide; D011744:Pyrimidinones; D011759:Pyrrolidines; D011943:Receptors, Adrenergic, beta; D050486:Serotonin Plasma Membrane Transport Proteins