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
We report herein the design and synthesis of a series of potent and selective GPR119 agonists. Our objective was to develop a GPR119 agonist with properties that were suitable for fixed-dose combination with a DPP4 inhibitor. Starting from a phenoxy analogue (1), medicinal chemistry efforts directed toward reducing half-life and increasing solubility led to the synthesis of a series of benzyloxy analogues. Compound 28 was chosen for further profiling because of its favorable physicochemical properties and excellent GPR119 potency across species. This compound exhibited a clean off-target profile in counterscreens and good in vivo efficacy in mouse oGTT.
