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jm6b00044_si_002.pdb (193.42 kB)

Structure-Based Design of 3‑(4-Aryl‑1H‑1,2,3-triazol-1-yl)-Biphenyl Derivatives as P2Y14 Receptor Antagonists

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posted on 2016-06-22, 19:13 authored by Anna Junker, Ramachandran Balasubramanian, Antonella Ciancetta, Elisa Uliassi, Evgeny Kiselev, Chiara Martiriggiano, Kevin Trujillo, Giorgi Mtchedlidze, Leah Birdwell, Kyle A. Brown, T. Kendall Harden, Kenneth A. Jacobson
UDP and UDP-glucose activate the P2Y14 receptor (P2Y14R) to modulate processes related to inflammation, diabetes, and asthma. A computational pipeline suggested alternatives to naphthalene of a previously reported P2Y14R antagonist (3, PPTN) using docking and molecular dynamics simulations on a hP2Y14R homology model based on P2Y12R structures. By reevaluating the binding of 3 to P2Y14R computationally, two alternatives, i.e., alkynyl and triazolyl derivatives, were identified. Improved synthesis of fluorescent antagonist 4 enabled affinity quantification (IC50s, nM) using flow cytometry of P2Y14R-expressing CHO cells. p-F3C-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 P2Y14R affinities agreed with predicted binding of alkynyl and triazole analogues. These triazoles, designed through a structure-based approach, can be assessed in disease models.

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