ABSTRACT
The discovery of vibegron, a potent and selective human ß3-AR agonist for the treatment of overactive bladder (OAB), is described. An early-generation clinical ß3-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 ß3-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.
Subject(s)
Adrenergic beta-3 Receptor Agonists/therapeutic use , Pyrimidinones/therapeutic use , Pyrrolidines/therapeutic use , Urinary Bladder, Overactive/drug therapy , Adrenergic beta-3 Receptor Agonists/pharmacokinetics , 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/toxicity , Pyrrolidines/pharmacokinetics , 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 , Urination/drug effects , X-Ray DiffractionABSTRACT
A series of conformationally restricted acetanilides were synthesized and evaluated as ß3-adrenergic receptor agonists (ß3-AR) for the treatment of overactive bladder (OAB). Optimization studies identified a five-membered ring as the preferred conformational lock of the acetanilide. Further optimization of both the aromatic and thiazole regions led to compounds such as 19 and 29, which have a good balance of potency and selectivity. These compounds have significantly reduced intrinsic clearance compared to our initial series of pyridylethanolamine ß3-AR agonists and thus have improved unbound drug exposures. Both analogues demonstrated dose dependent ß3-AR mediated responses in a rat bladder hyperactivity model.
