Exploration of Alternative Scaffolds for P2Y14 Receptor Antagonists Containing a Biaryl Core

作者：Kwan‐Young Jung, Jinha Yu, Zhiwei Wen, Veronica Salmaso, Tadeusz P. Karcz, Ngan Bao Phung, Zhoumou Chen, Sierra Duca, John M. Bennett, Steven P. Dudas, Daniela Salvemini, Zhan‐Guo Gao, Donald N. Cook, Kenneth A. Jacobson · 发表于：Journal of Medicinal Chemistry · 年份：2020 · DOI：10.1021/acs.jmedchem.0c00745 · 被引用次数：35 · 研究领域：Adenosine and Purinergic Signaling、Synthesis and Biological Evaluation、Pharmacological Receptor Mechanisms and Effects

Various heteroaryl and bicyclo-aliphatic analogues of zwitterionic biaryl P2Y 14 receptor (P2Y 14 R) antagonists were synthesized, and affinity was measured in P2Y 14 R-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 P2Y 14 R 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, IC 50 ≈ 20 nM at hP2Y 14 R/mP2Y 14 R), 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 P2Y 14 R antagonist structure–activity relationship, introducing diverse physical–chemical properties.