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.

Miniaturization and parallel processing play an important role in the evolution of many technologies. We demonstrate the application of miniaturized high-throughput experimentation methods to resolve synthetic chemistry challenges on the frontlines of a lead optimization effort to develop diacylglycerol acyltransferase (DGAT1) inhibitors. Reactions were performed on ∼1 mg scale using glass microvials providing a miniaturized high-throughput experimentation capability that was used to study a challenging SAr reaction. The availability of robust synthetic chemistry conditions discovered in these miniaturized investigations enabled the development of structure-activity relationships that ultimately led to the discovery of soluble, selective, and potent inhibitors of DGAT1.

This report describes the discovery of a potent, orally bioavailable CC chemokine receptor 2 (CCR2) antagonist which, while optimized for CCR2 potency, also had potent CC chemokine receptor 5 (CCR5) activity.

A ruthenium-catalyzed carboxylative cyclization of 1,6-diynes has been developed. In the presence of catalytic amounts of [Ru(p-cymeme)Cl2]2 (2.5 mol %), P(4-F-C6H4)3 (7.5 mol %) and 4-dimethylaminopyridine (10 mol %), a variety of carboxylic acids condense with 1,6-terminal diynes to give rise to cyclohexylidene enol carboxylates as the products with exclusive (E)-selectivity. A set of control experiments suggests that the reaction proceeds through a mechanism involving an anti attack of the carboxylate nucleophile on the π-alkyne coordinated to a ruthenium vinylidene complex. Thus, the new reaction achieves C−C bond formation through a dual mode of alkyne activationvinylidene formation and π-complexationmediated by a single ruthenium(II) catalyst.

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