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Discovery, design and synthesis of the first reported potent and selective sphingosine-1-phosphate 4 (S1P4) receptor antagonists |
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| Authors: | Guerrero Miguel Urbano Mariangela Velaparthi Subash Zhao Jian Schaeffer Marie-Therese Brown Steven Rosen Hugh Roberts Edward |
| Affiliation: | a Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, United States b Department of Immunology, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, United States c The Scripps Research Institute Molecular Screening Center, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, United States |
| Abstract: | Selective S1P4 receptor antagonists could be novel therapeutic agents for the treatment of influenza infection in addition to serving as a useful tool for understanding S1P4 receptor biological functions. 5-(2,5-Dichlorophenyl)-N-(2,6-dimethylphenyl)furan-2-carboxamide was identified from screening the Molecular Libraries-Small Molecule Repository (MLSMR) collection and selected as a promising S1P4 antagonist hit with moderate in vitro potency and high selectivity against the other family receptor subtypes (S1P1-3,5). Rational chemical modifications of the hit allowed the disclosure of the first reported highly selective S1P4 antagonists with low nanomolar activity and adequate physicochemical properties suitable for further lead-optimization studies. |
| Keywords: | S1P4 receptor antagonists S1P1-3,5 receptor family 5-Aryl furan-2-arylcarboxamide |
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