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.

β3‐Adrenoceptors in the normal and diseased urinary bladder—What are the open questions?

“…Vibegron (MK‐4618) is a β 3 ‐adrenoceptor agonist, potently activates human β 3 ‐adrenoceptors with an EC 50 value of 1.1 nM, and vibegron is also highly selective over β 1 ‐ and β 2 ‐adrenoceptors versus β 3 ‐adrenoceptors across multiple species (Table ). Vibegron did not show any stimulating or inhibitory effects on cytochrome P450 enzymes, suggesting a low risk of drug–drug interaction (Edmondson et al, ). A recent randomized placebo‐controlled Phase III study showed that the 12‐week treatment with vibegron (50 or 100 mg once daily) resulted in a significant improvement over the placebo in changes in the mean number of micturitions per day at Week 12 from baseline (primary endpoint) and changes from baselines in OAB symptom variables (daily episodes of urgency, urgency incontinence, incontinence, and nocturia, and voided volume/micturition) as the secondary endpoints.…”

Efficacy of novel β3‐adrenoreceptor agonist vibegron on nocturia in patients with overactive bladder: A post‐hoc analysis of a randomized, double‐blind, placebo‐controlled phase 3 study

“…Mirabegron, a CYP2D6 inhibitor, has been reported to have off‐target effects, whereas vibegron is metabolized independently from CYP3A4, 2D6 or 2C9, and is thus considered less likely to cause drug–drug interactions. Vibegron is also reported to be highly selective to cardiac ion channels (hERG, hCav1.2 and hNav1.5) and serotonin transporters …”

“…A β 3 ‐adrenoreceptor agonist causes smooth muscle relaxation in the bladder to increase the bladder capacity, and has attracted attention as a new therapeutic drug for OAB . Vibegron is a novel, potent and selective β 3 ‐adrenoreceptor agonist, and exerts excellent pharmacological activity ( in vitro and in vivo ) . Recently, a phase 3 study in Japanese OAB patients was carried out, and showed excellent efficacy and high tolerability of vibegron when compared with a placebo .…”

Long‐term safety and efficacy of the novel β3‐adrenoreceptor agonist vibegron in Japanese patients with overactive bladder: A phase III prospective study

“…Vibegron is a novel, potent and selective β 3 ‐AR agonist, and possesses favorable preclinical pharmacokinetic, pharmacological and toxicological profiles in vitro and in vivo as a candidate drug for OAB . Especially regarding drug metabolism, vibegron did not show any induction and inhibitory effect on cytochrome P450 enzymes, suggesting a low risk of drug–drug interaction .…”

“…Vibegron is a novel, potent and selective β 3 ‐AR agonist, and possesses favorable preclinical pharmacokinetic, pharmacological and toxicological profiles in vitro and in vivo as a candidate drug for OAB . Especially regarding drug metabolism, vibegron did not show any induction and inhibitory effect on cytochrome P450 enzymes, suggesting a low risk of drug–drug interaction . In a phase 2b placebo‐controlled randomized clinical trial, treatments with vibegron 50 mg and 100 mg for 8 weeks in patients with OAB were generally well‐tolerated and showed improvements in OAB symptoms (NCT01314872: https://clinicaltrials.gov/ct2/show/results/NCT01314872).…”