title: Discovery, design and synthesis of a selective S1P(3) receptor allosteric agonist.
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.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd, La Jolla, CA 92037, United States.
authors.forename: Miguel
authors.initials: M
authors.lastname: Guerrero
authors.forename: Ramulu
authors.initials: R
authors.lastname: Poddutoori
authors.forename: Mariangela
authors.initials: M
authors.lastname: Urbano
authors.forename: Xuemei
authors.initials: X
authors.lastname: Peng
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Spicer
authors.forename: Peter S
authors.initials: PS
authors.lastname: Chase
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hodder
authors.forename: Marie-Therese
authors.initials: MT
authors.lastname: Schaeffer
authors.forename: Steven
authors.initials: S
authors.lastname: Brown
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.forename: Edward
authors.initials: E
authors.lastname: Roberts
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D001393:Azoles / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000096:biosynthesis; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D001393:Azoles; D007166:Immunosuppressive Agents; D008024:Ligands; D049349:Receptors, Lysosphingolipid
keywords: Allosteric agonist; Cardiovascular functions; S1P(3) receptor