Conformationally Constrained <i>ortho-</i>Anilino Diaryl Ureas: Discovery of 1‑(2-(1′-Neopentylspiro[indoline-3,4′-piperidine]-1-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea, a Potent, Selective, and Bioavailable P2Y₁ Antagonist

Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y₁ antagonists are efficacious as antiplatelet agents and may offer a safety advantage over P2Y₁₂ antagonists in terms of reduced bleeding liabilities. In this article, we describe the structural modification of the <i>tert</i>-butyl phenoxy portion of lead compound <b>1</b> and the subsequent discovery of a novel series of conformationally constrained <i>ortho</i>-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted diaryl ureas are described as potent, orally bioavailable small-molecule P2Y₁ antagonists with improved activity in functional assays and improved oral bioavailability in rats. Homology modeling and rat PK/PD studies on benchmark compound <b>3l</b> will also be presented. Compound <b>3l</b> was our first P2Y₁ antagonist to demonstrate a robust oral antithrombotic effect with mild bleeding liability in the rat thrombosis and hemostasis models

Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode

A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-<i>cis</i>-CF₃ to the pyrrolidine improves the human GPR40 binding <i>K</i>_i and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers <b>(</b><i><b>R,R</b></i><b>)-68</b> and <b>(</b><i><b>S,S</b></i><b>)-68</b> have differential effects on the radioligand used for the binding assay, with <b>(</b><i><b>R,R</b></i><b>)-68</b> potentiating the radioligand and <b>(</b><i><b>S,S</b></i><b>)-68</b> displacing the radioligand. Compound <b>(</b><i><b>R</b></i>,<i><b>R</b></i><b>)-68</b> activates both G_q-coupled intracellular Ca²⁺ flux and G_s-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound <b>(</b><i><b>R</b></i>,<i><b>R</b></i><b>)-68</b>, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound <b>(</b><i><b>R</b></i>,<i><b>R</b></i><b>)-68</b> significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series