Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10591306 | Bioorganic & Medicinal Chemistry Letters | 2013 | 4 Pages |
Abstract
Potent and selective S1P3 receptor (S1P3-R) agonists may represent important proof-of-principle tools used to clarify the receptor biological function and assess the therapeutic potential of the S1P3-R in cardiovascular, inflammatory and pulmonary diseases. N,N-Dicyclohexyl-5-propylisoxazole-3-carboxamide was identified by a high-throughput screening of MLSMR library as a promising S1P3-R agonist. Rational chemical modifications of the hit allowed the identification of N,N-dicyclohexyl-5-cyclopropylisoxazole-3-carboxamide, a S1P3-R agonist endowed with submicromolar activity and exquisite selectivity over the remaining S1P1,2,4,5-R family members. A combination of ligand competition, site-directed mutagenesis and molecular modeling studies showed that the N,N-dicyclohexyl-5-cyclopropylisoxazole-3-carboxamide is an allosteric agonist and binds to the S1P3-R in a manner that does not disrupt the S1P3-R-S1P binding. The lead molecule herein disclosed constitutes a valuable pharmacological tool to explore the molecular basis of the receptor function, and provides the bases for further rational design of more potent and drug-like S1P3-R allosteric agonists.
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Authors
Miguel Guerrero, Ramulu Poddutoori, Mariangela Urbano, Xuemei Peng, Timothy P. Spicer, Peter S. Chase, Peter S. Hodder, Marie-Therese Schaeffer, Steven Brown, Hugh Rosen, Edward Roberts,