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Design,synthesis and SAR analysis of novel potent and selective small molecule antagonists of NPBWR1 (GPR7) |
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| Authors: | Mariangela Urbano Miguel Guerrero Jian Zhao Subash Velaparthi S Adrian Saldanha Peter Chase Zhiwei Wang Olivier Civelli Peter Hodder Marie-Therese Schaeffer Steven Brown Hugh Rosen Edward Roberts |
| Institution: | 1. Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, United States;2. Scripps Research Institute Molecular Screening Center, Lead Identification Division, Translational Research Institute, 130 Scripps Way, Jupiter, FL 33458, United States;3. Department of Pharmacology, University of California Irvine, Irvine, CA 92697, United States;4. Department of Molecular Therapeutics, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, United States;5. Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, United States;6. The Scripps Research Institute Molecular Screening Center, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, United States;7. Department of Immunology, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, United States |
| Abstract: | Novel small molecule antagonists of NPBWR1 (GPR7) are herein reported. A high-throughput screening (HTS) of the Molecular Libraries-Small Molecule Repository library identified 5-chloro-4-(4-methoxyphenoxy)-2-(p-tolyl)pyridazin-3(2H)-one as a NPBWR1 hit antagonist with micromolar activity. Design, synthesis and structure–activity relationships study of the HTS-derived hit led to the identification of 5-chloro-2-(3,5-dimethylphenyl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one lead molecule with submicromolar antagonist activity at the target receptor and high selectivity against a panel of therapeutically relevant off-target proteins. This lead molecule may provide a pharmacological tool to clarify the molecular basis of the in vivo physiological function and therapeutic utility of NPBWR1 in diverse disease areas including inflammatory pain and eating disorders. |
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