title: Structure-Based Design of 3-(4-Aryl-1H-1,2,3-triazol-1-yl)-Biphenyl Derivatives as P2Y14 Receptor Antagonists.
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.
authors.affiliation: 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.
authors.forename: Anna
authors.initials: A
authors.lastname: Junker
authors.affiliation: 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.
authors.forename: Ramachandran
authors.initials: R
authors.lastname: Balasubramanian
authors.affiliation: 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.
authors.forename: Antonella
authors.initials: A
authors.lastname: Ciancetta
authors.affiliation: 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.
authors.forename: Elisa
authors.initials: E
authors.lastname: Uliassi
authors.affiliation: 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.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Kiselev
authors.affiliation: 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.
authors.forename: Chiara
authors.initials: C
authors.lastname: Martiriggiano
authors.affiliation: 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.
authors.forename: Kevin
authors.initials: K
authors.lastname: Trujillo
authors.affiliation: 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.
authors.forename: Giorgi
authors.initials: G
authors.lastname: Mtchedlidze
authors.affiliation: 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.
authors.forename: Leah
authors.initials: L
authors.lastname: Birdwell
authors.affiliation: Department of Pharmacology, University of North Carolina, School of Medicine , Chapel Hill, North Carolina 27599, United States.
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Brown
authors.affiliation: Department of Pharmacology, University of North Carolina, School of Medicine , Chapel Hill, North Carolina 27599, United States.
authors.forename: T Kendall
authors.initials: TK
authors.lastname: Harden
authors.affiliation: 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.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D058919:Purinergic P2 Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D001713:Biphenyl Compounds; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D014230:Triazoles; C518528:P2Y14 receptor, human; C010574:biphenyl