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

Title
Exploration of Alternative Scaffolds for P2Y14 Receptor Antagonists Containing a Biaryl Core
Authors
유진하Young-Hwan JungZhiwei WenVeronica SalmasoTadeusz P. KarczNgan B. PhungZhoumou ChenSierra DucaJohn M. BennettSteven DudasDaniela SalveminiZhan-Guo GaoDonald N. CookKenneth A. Jacobson
Issue Date
2020-09
Publisher
Journal of medicinal chemistry
Citation
VOL 63, NO 17-9589
Abstract
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.
URI
http://pubs.kist.re.kr/handle/201004/72204
ISSN
0022-2623
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KIST Publication > Article
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