Exploration of Alternative Scaffolds for P2Y14 Receptor Antagonists Containing a Biaryl Core
- Exploration of Alternative Scaffolds for P2Y14 Receptor Antagonists Containing a Biaryl Core
- 유진하; Young-Hwan Jung; 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
- Issue Date
- Journal of medicinal chemistry
- VOL 63, NO 17-9589
- 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.
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