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

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

doi:10.1021/acs.jmedchem.5b01372

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

J Med Chem. 2016 Jan 28;59(2):609-23. doi: 10.1021/acs.jmedchem.5b01372. Epub 2016 Jan 8.

Authors

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

Affiliation

¹ Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.

PMID: 26709102
DOI: 10.1021/acs.jmedchem.5b01372

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.

MeSH terms

Adrenergic beta-3 Receptor Agonists / pharmacokinetics
Adrenergic beta-3 Receptor Agonists / therapeutic use*
Adrenergic beta-3 Receptor Agonists / toxicity
Animals
CHO Cells
Cricetinae
Cricetulus
Drug Discovery
Female
Humans
Lipidoses / chemically induced
Microsomes, Liver / drug effects
Microsomes, Liver / enzymology
Models, Molecular
Pyrimidinones / pharmacokinetics
Pyrimidinones / therapeutic use*
Pyrimidinones / toxicity
Pyrrolidines / pharmacokinetics
Pyrrolidines / therapeutic use*
Pyrrolidines / toxicity
Rats
Rats, Sprague-Dawley
Receptors, Adrenergic, beta / drug effects
Receptors, Adrenergic, beta / metabolism
Serotonin Plasma Membrane Transport Proteins / metabolism
Structure-Activity Relationship
Urinary Bladder / drug effects
Urinary Bladder, Overactive / drug therapy*
Urination / drug effects
X-Ray Diffraction

Substances

Adrenergic beta-3 Receptor Agonists
N-(4-((5-(hydroxy(phenyl)methyl)pyrrolidin-2-yl)methyl)phenyl)-4-oxo-4,6,7,8-tetrahydropyrrolo(1,2-a)pyrimidine-6-carboxamide
Pyrimidinones
Pyrrolidines
Receptors, Adrenergic, beta
Serotonin Plasma Membrane Transport Proteins