title: Pharmacological Characterization of a Novel Beta 3 Adrenergic Agonist, Vibegron: Evaluation of Antimuscarinic Receptor Selectivity for Combination Therapy for Overactive Bladder.
abstract: Although the physiologic role of muscarinic receptors in bladder function and the therapeutic efficacy of muscarinic antagonists for the treatment of overactive bladder are well established, the role of β3-adrenergic receptors (β3ARs) and their potential as therapeutics is just emerging. In this manuscript, we characterized the pharmacology of a novel β3AR agonist vibegron (MK-4618, KRP-114V) and explored mechanistic interactions of β3AR agonism and muscarinic antagonism in urinary bladder function. Vibegron is a potent, selective full β3AR agonist across species, and it dose dependently increased bladder capacity, decreased micturition pressure, and increased bladder compliance in rhesus monkeys. The relaxation effect of vibegron was enhanced when combined with muscarinic antagonists, but differentially influenced by muscarinic receptor subtype selectivity. The effect was greater when vibegron was co-administered with tolterodine, a nonselective antagonist, compared with coadministration with darifenacin, a selective M3 antagonist. Furthermore, a synergistic effect for bladder strip relaxation was observed with the combination of a β3AR agonist and tolterodine in contrast to simple additivity with darifenacin. To determine expression in rhesus bladder, we employed a novel β3AR agonist probe, [3H]MRL-037, that selectively labels β3receptors in both urothelium and detrusor smooth muscle. Vibegron administration caused a dose-dependent increase in circulating glycerol and fatty acid levels in rhesus and rat in vivo, suggesting these circulating lipids can be surrogate biomarkers. The translation of our observation to the clinic has yet to be determined, but the combination of β3AR agonists with M2/M3 antimuscarinics has the potential to redefine the standard of care for the pharmacological treatment of overactive bladder.
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Kenilworth, New Jersey jerry.disalvo@evotec.com.
authors.forename: J
authors.initials: J
authors.lastname: Di Salvo
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: H
authors.initials: H
authors.lastname: Nagabukuro
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: L A
authors.initials: LA
authors.lastname: Wickham
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: C
authors.initials: C
authors.lastname: Abbadie
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: J A
authors.initials: JA
authors.lastname: DeMartino
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: A
authors.initials: A
authors.lastname: Fitzmaurice
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: L
authors.initials: L
authors.lastname: Gichuru
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: A
authors.initials: A
authors.lastname: Kulick
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: M J
authors.initials: MJ
authors.lastname: Donnelly
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: N
authors.initials: N
authors.lastname: Jochnowitz
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: A L
authors.initials: AL
authors.lastname: Hurley
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: A
authors.initials: A
authors.lastname: Pereira
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: A
authors.initials: A
authors.lastname: Sanfiz
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: G
authors.initials: G
authors.lastname: Veronin
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: K
authors.initials: K
authors.lastname: Villa
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: J
authors.initials: J
authors.lastname: Woods
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: B
authors.initials: B
authors.lastname: Zamlynny
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: E
authors.initials: E
authors.lastname: Zycband
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: G M
authors.initials: GM
authors.lastname: Salituro
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: T
authors.initials: T
authors.lastname: Frenkl
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: A E
authors.initials: AE
authors.lastname: Weber
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: S D
authors.initials: SD
authors.lastname: Edmondson
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: M
authors.initials: M
authors.lastname: Struthers
mesh_terms: D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D009130:Muscle, Smooth / Q000187:drug effects / Q000503:physiopathology; D021381:Protein Transport / Q000187:drug effects; D011744:Pyrimidinones / Q000494:pharmacology* / Q000627:therapeutic use; D011759:Pyrrolidines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism*; D013045:Species Specificity; D001743:Urinary Bladder / Q000187:drug effects / Q000503:physiopathology; D053201:Urinary Bladder, Overactive / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D014563:Urodynamics / Q000187:drug effects
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D018727:Muscarinic Antagonists; 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; D022702:Receptors, Adrenergic, beta-3