- Discovery, design and synthesis of a selective S1P3 receptor allosteric agonist
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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 S1P 3-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.
- Guerrero, Miguel,Poddutoori, Ramulu,Urbano, Mariangela,Peng, Xuemei,Spicer, Timothy P.,Chase, Peter S.,Hodder, Peter S.,Schaeffer, Marie-Therese,Brown, Steven,Rosen, Hugh,Roberts, Edward
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p. 6346 - 6349
(2013/11/19)
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- MACROCYCLIC SERINE PROTEASE INHIBITORS USEFUL AGAINST VIRAL INFECTIONS, PARTICULARLY HCV
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Provided herein are macrocyclic serine protease inhibitor compounds, for example, of Formula (Ia) or (Ib), pharmaceutical compositions comprising the compounds, and processes of preparation thereof. Also provided are methods of their use for the treatment of an HCV infection in a host in need thereof.
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Page/Page column 156
(2011/02/24)
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