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Article 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.
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Comparison of efficacy and safety of mirabegron and vibegron in the treatment of Overactive Bladder (OAB) in older women: A systematic review and meta-analysis.
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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 β-adrenergic receptors (βARs) and their potential as therapeutics is just emerging. In this manuscript, we characterized the pharmacology of a novel βAR agonist vibegron (MK-4618, KRP-114V) and explored mechanistic interactions of βAR agonism and muscarinic antagonism in urinary bladder function. Vibegron is a potent, selective full βAR agonist across species, and it dose dependently increased bladder capacity, decreased micturition pressure, and increased bladder compliance in rhesus monkeys.
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Merck Research Laboratories , 2015 Galloping Hill Road, PO Box 539, Kenilworth, New Jersey 07033, United States.
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.
View Article and Find Full Text PDF