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Exploration of Alternative Scaffolds for P2Y 14 Receptor Antagonists Containing a Biaryl Core.

التفاصيل البيبلوغرافية
العنوان: Exploration of Alternative Scaffolds for P2Y 14 Receptor Antagonists Containing a Biaryl Core.
المؤلفون: Jung YH; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States., Yu J; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States., Wen Z; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States., Salmaso V; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States., Karcz TP; Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, North Carolina 27709, United States.; Jagiellonian University, Kraków31-007, Poland., Phung NB; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States., Chen Z; Department of Pharmacology and Physiology and the Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University School of Medicine, 1402 South Grand Boulevard, Saint Louis, Missouri 63104, United States., Duca S; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States., Bennett JM; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States., Dudas S; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States., Salvemini D; Department of Pharmacology and Physiology and the Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University School of Medicine, 1402 South Grand Boulevard, Saint Louis, Missouri 63104, United States., Gao ZG; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States., Cook DN; Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, North Carolina 27709, United States., Jacobson KA; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States.
المصدر: Journal of medicinal chemistry [J Med Chem] 2020 Sep 10; Vol. 63 (17), pp. 9563-9589. Date of Electronic Publication: 2020 Aug 06.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
مواضيع طبية MeSH: Drug Design*, Purinergic P2 Receptor Antagonists/*chemistry , Purinergic P2 Receptor Antagonists/*pharmacology , Receptors, Purinergic P2/*metabolism , Triazoles/*chemistry , Triazoles/*pharmacology, Animals ; HEK293 Cells ; Humans ; Inhibitory Concentration 50 ; Mice ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Neuralgia/drug therapy ; Protein Conformation ; Purinergic P2 Receptor Antagonists/metabolism ; Purinergic P2 Receptor Antagonists/therapeutic use ; Receptors, Purinergic P2/chemistry ; Solubility ; Structure-Activity Relationship ; Triazoles/metabolism ; Triazoles/therapeutic use
مستخلص: 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.
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معلومات مُعتمدة: Z01 DK031126 United States ImNIH Intramural NIH HHS; HHSN271200800025C United States MH NIMH NIH HHS; ZIA DK031116 United States ImNIH Intramural NIH HHS; Z01 DK031116 United States ImNIH Intramural NIH HHS; ZIA ES102025 United States ImNIH Intramural NIH HHS
المشرفين على المادة: 0 (P2Y14 receptor, human)
0 (Purinergic P2 Receptor Antagonists)
0 (Receptors, Purinergic P2)
0 (Triazoles)
تواريخ الأحداث: Date Created: 20200814 Date Completed: 20201211 Latest Revision: 20210911
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC8040948
DOI: 10.1021/acs.jmedchem.0c00745
PMID: 32787142
قاعدة البيانات: MEDLINE
الوصف
تدمد:1520-4804
DOI:10.1021/acs.jmedchem.0c00745