Discovery, synthesis and SAR analysis of novel selective small molecule S1P(4)-R agonists based on a (2Z,5Z)-5-((pyrrol-3-yl)methylene)-3-alkyl-2-(alkylimino)thiazolidin-4-o ne chemotype

作者：Urbano Mariangela; Guerrero Miguel; Velaparthi Subash; Crisp Melissa; Chase Peter; Hodder Peter; Schaeffer Marie Therese; Brown Steven; Rosen Hugh; Roberts Edward^*

来源：Bioorganic & Medicinal Chemistry Letters, 2011, 21(22): 6739-6745.

DOI：10.1016/j.bmcl.2011.09.049

• S1P(4) receptor
• Selective small molecule S1P(4)-R agonists
• Thrombocytopenia
• Viral infections

High affinity and selective S1P(4) receptor (S1P(4)-R) small molecule agonists may be important proof-of-principle tools used to clarify the receptor biological function and effects to assess the therapeutic potential of the S1P4-R in diverse disease areas including treatment of viral infections and thrombocytopenia. A high-throughput screening campaign of the Molecular Libraries-Small Molecule Repository was carried out by our laboratories and identified (2Z,5Z)-5-((1-(2-fluorophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene)-3-methyl-2-(methylimino) thiazolidin-4-one as a promising S1P(4)-R agonist hit distinct from literature S1P(4)-R modulators. Rational chemical modifications of the hit allowed the identification of a promising lead molecule with low nanomolar S1P(4)-R agonist activity and exquisite selectivity over the other S1P(1-3,5)-Rs family members. The lead molecule herein disclosed constitutes a valuable pharmacological tool to explore the effects of the S1P(4)-R signaling cascade and elucidate the molecular basis of the receptor function.

• 出版日期2011-11-15