Discovery, synthesis and SAR analysis of novel selective small molecule S1P sub(4-R agonists based on a (2Z,5Z)-5-((pyrrol-3-yl)methylene)-3-alkyl-2-(alkylimino)thiazolid i n-4-one chemotype)

• Published in: Bioorganic & medicinal chemistry letters 2011-11, Vol.21 (22), p.6739-6745
• Main Authors: Urbano, Mariangela, Guerrero, Miguel, Velaparthi, Subash, Crisp, Melissa, Chase, Peter, Hodder, Peter, Schaeffer, Marie-Therese, Brown, Steven, Rosen, Hugh, Roberts, Edward
• Format: Article
• Language: English
• Subjects: Chemical modification
• ISSN: 0960-894X
• DOI: 10.1016/j.bmcl.2011.09.049

High affinity and selective S1P sub(4 receptor (S1P) sub(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 sub(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)methyle n e)-3-methyl-2-(methylimino) thiazolidin-4-one as a promising S1P) sub(4)-R agonist hit distinct from literature S1P sub(4-R modulators. Rational chemical modifications of the hit allowed the identification of a promising lead molecule with low nanomolar S1P) sub(4)-R agonist activity and exquisite selectivity over the other S1P sub(1-3,5-Rs family members. The lead molecule herein disclosed constitutes a valuable pharmacological tool to explore the effects of the S1P) sub(4)-R signaling cascade and elucidate the molecular basis of the receptor function.