Structure-Based Design of 3-(4-Aryl-1H-1,2,3-triazol-1-yl)-Biphenyl Derivatives as P2Y(14) Receptor Antagonists

[Image: see text] UDP and UDP-glucose activate the P2Y(14) receptor (P2Y(14)R) to modulate processes related to inflammation, diabetes, and asthma. A computational pipeline suggested alternatives to naphthalene of a previously reported P2Y(14)R antagonist (3, PPTN) using docking and molecular dynamics simulations on a hP2Y(14)R homology model based on P2Y(12)R structures. By reevaluating the binding of 3 to P2Y(14)R computationally, two alternatives, i.e., alkynyl and triazolyl derivatives, were identified. Improved synthesis of fluorescent antagonist 4 enabled affinity quantification (IC(50)s, nM) using flow cytometry of P2Y(14)R-expressing CHO cells. p-F(3)C-phenyl-triazole 65 (32) was more potent than a corresponding alkyne 11. Thus, additional triazolyl derivatives were prepared, as guided by docking simulations, with nonpolar aryl substituents favored. Although triazoles were less potent than 3 (6), simpler synthesis facilitated further structural optimization. Additionally, relative P2Y(14)R affinities agreed with predicted binding of alkynyl and triazole analogues. These triazoles, designed through a structure-based approach, can be assessed in disease models.