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Bridged Piperidine Analogues of a High Affinity Naphthalene-Based P2Y14R Antagonist.
Wen, Zhiwei; Salmaso, Veronica; Jung, Young-Hwan; Phung, Ngan B; Gopinatth, Varun; Shah, Qasim; Patterson, Alexandra T; Randle, John C R; Chen, Zhoumou; Salvemini, Daniela; Lieberman, David I; Whitehead, Gregory S; Karcz, Tadeusz P; Cook, Donald N; Jacobson, Kenneth A.
Affiliation
  • 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.
  • 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.
  • 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.
  • Gopinatth 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.
  • Shah Q; 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.
  • Patterson AT; 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.
  • Randle JCR; Random Walk Ventures, LLC, 108 Lincoln Street Unit 6B, Boston, Massachusetts 02111, 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, St. Louis, Missouri 63104, 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, St. Louis, Missouri 63104, United States.
  • Lieberman DI; 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.
  • Whitehead GS; Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, United States.
  • Karcz TP; Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, United States.
  • Cook DN; Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, 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.
J Med Chem ; 65(4): 3434-3459, 2022 02 24.
Article in En | MEDLINE | ID: mdl-35113556
High affinity phenyl-piperidine P2Y14R antagonist 1 (PPTN) was modified with piperidine bridging moieties to probe receptor affinity and hydrophobicity. Various 2-azanorbornane, nortropane, isonortropane, isoquinuclidine, and ring-opened cyclopentylamino derivatives preserved human P2Y14R affinity (fluorescence binding assay), and their pharmacophoric overlay was compared. Enantiomeric 2-azabicyclo[2.2.1]hept-5-en-3-one precursors assured stereochemically unambiguous, diverse products. Pure (S,S,S) 2-azanorbornane enantiomer 15 (MRS4738) displayed higher affinity than 1 (3-fold higher affinity than enantiomer 16) and in vivo antihyperallodynic and antiasthmatic activity. Its double prodrug 143 (MRS4815) dramatically reduced lung inflammation in a mouse asthma model. Related lactams 21-24 and dicarboxylate 42 displayed intermediate affinity and enhanced aqueous solubility. Isoquinuclidine 34 (IC50 15.6 nM) and isonortropanol 30 (IC50 21.3 nM) had lower lipophilicity than 1. In general, rigidified piperidine derivatives did not lower lipophilicity dramatically, except those rings with multiple polar groups. P2Y14R molecular modeling based on a P2Y12R structure showed stable and persistent key interactions for compound 15.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Piperidines / Purinergic P2 Receptor Antagonists Limits: Animals Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2022 Document type: Article Affiliation country: United States Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Piperidines / Purinergic P2 Receptor Antagonists Limits: Animals Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2022 Document type: Article Affiliation country: United States Country of publication: United States