Discovery, synthesis and SAR analysis of novel selective small molecule S1P4-R agonists based on a (2Z,5Z)-5-((pyrrol-3-yl)methylene)-3-alkyl-2-(alkylimino)thiazolidin-4-one chemotype

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 S1P(4)-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.