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

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

  • J Med Chem. 2016 Jul 14;59(13):6149-68. doi: 10.1021/acs.jmedchem.6b00044.
Anna Junker 1 Ramachandran Balasubramanian 1 Antonella Ciancetta 1 Elisa Uliassi 1 Evgeny Kiselev 1 Chiara Martiriggiano 1 Kevin Trujillo 1 Giorgi Mtchedlidze 1 Leah Birdwell 1 Kyle A Brown 2 T Kendall Harden 2 Kenneth A Jacobson 1
Affiliations

Affiliations

  • 1 Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, Maryland 20892-0810, United States.
  • 2 Department of Pharmacology, University of North Carolina, School of Medicine , Chapel Hill, North Carolina 27599, United States.
Abstract

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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