SAR analysis of innovative selective small molecule antagonists of sphingosine-1-phosphate 4 (S1P₄) receptor.

SAR analysis of innovative HTS-derived 5-aryl furan-2-arylcarboxamide antagonists of the S1P4 receptor allowed the elucidation of the putative binding requirements of the central furan moiety. Molecular diversity within the hit class was increased, and novel nanomolar affinity S1P4 antagonists with high selectivity against the SIP1–3,5 family members were developed. Remarkably, thiophene and phenyl derivative 19, 47 (CYM50333, CYM50367), represent valuable small molecule tools for in vivo pharmacological validation of the target receptor in megakaryocyte differentiation and immunopathological response to airway viral infections.