Exploration of Alternative Scaffolds for P2Y14 Receptor Antagonists Containing a Biaryl Core
journal contributionposted on 06.08.2020, 22:21 by Young-Hwan Jung, Jinha Yu, Zhiwei Wen, Veronica Salmaso, Tadeusz P. Karcz, Ngan B. Phung, Zhoumou Chen, Sierra Duca, John M. Bennett, Steven Dudas, Daniela Salvemini, Zhan-Guo Gao, Donald N. Cook, Kenneth A. Jacobson
Various heteroaryl and bicyclo-aliphatic analogues of zwitterionic biaryl P2Y14 receptor (P2Y14R) antagonists were synthesized, and affinity was measured in P2Y14R-expressing Chinese hamster ovary cells by flow cytometry. Given this series’ low water solubility, various polyethylene glycol derivatives of the distally binding piperidin-4-yl moiety of moderate affinity were synthesized. Rotation of previously identified 1,2,3-triazole attached to the central m-benzoic acid core (25) provided moderate affinity but not indole and benzimidazole substitution of the aryl-triazole. The corresponding P2Y14R region is predicted by homology modeling as a deep, sterically limited hydrophobic pocket, with the outward pointing piperidine moiety being the most flexible. Bicyclic-substituted piperidine ring derivatives of naphthalene antagonist 1, e.g., quinuclidine 17 (MRS4608, IC50 ≈ 20 nM at hP2Y14R/mP2Y14R), or of triazole 2, preserved affinity. Potent antagonists 1, 7a, 17, and 23 (10 mg/kg) protected in an ovalbumin/Aspergillus mouse asthma model, and PEG conjugate 12 reduced chronic pain. Thus, we expanded P2Y14R antagonist structure–activity relationship, introducing diverse physical–chemical properties.
Read the peer-reviewed publication
piperidine moietyaffinitybenzoic acid coredistally binding piperidin -4-yl moietyMRSzwitterionic biaryl P 2Y 14 receptorP 2Y 14 R-expressinghomology modelingnaphthalene antagonist 1Potent antagonists 1Bicyclic-substituted piperidine rin...water solubilityflow cytometryPEG conjugate 12Biaryl CoreP 2Y 14 R regionbicyclo-aliphatic analogueshamster ovary cellsbenzimidazole substitutionAlternative Scaffoldstriazole 2polyethylene glycol derivativesICP 2Y 14 RP 2Y 14 Receptor Antagonists Containing