Discovery of Chromane Propionic Acid Analogues as Selective Agonists of GPR120 with <i>in Vivo</i> Activity in Rodents

GPR120 (FFAR4) is a fatty acid sensing G protein coupled receptor (GPCR) that has been identified as a target for possible treatment of type 2 diabetes. A selective activator of GPR120 containing a chromane scaffold has been designed, synthesized, and evaluated <i>in vivo</i>. Results of these efforts suggest that chromane propionic acid <b>18</b> is a suitable tool molecule for further animal studies. Compound <b>18</b> is selective over the closely related target GPR40 (FFAR1), has a clean off-target profile, demonstrates suitable pharmacokinetic properties, and has been evaluated in wild-type/knockout GPR120 mouse oGTT studies

Discovery of Vibegron: A Potent and Selective β₃ Adrenergic Receptor Agonist for the Treatment of Overactive Bladder

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 (<b>3</b>) 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

Design of Potent and Orally Active GPR119 Agonists for the Treatment of Type II Diabetes

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 (<b>1</b>), medicinal chemistry efforts directed toward reducing half-life and increasing solubility led to the synthesis of a series of benzyloxy analogues. Compound <b>28</b> 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 <i>in vivo</i> efficacy in mouse oGTT