期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 63, 期 17, 页码 9563-9589出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c00745
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资金
- NIDDK [ZIA DK031116]
- NIEHS [ZIAES102025]
- Kantum Diagnostics (Belmont, NH)
- National Institute of Mental Health's Psychoactive Drug Screening Program (Univ. North Carolina at Chapel Hill) [HHSN-271-2008-00025-C]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [ZIADK031116] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [ZIAES102025] Funding Source: NIH RePORTER
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, IC50 approximate to 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.
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