Discovery, design and synthesis of the first reported potent and selective sphingosine-1-phosphate 4 (S1P4) receptor antagonists

Selective S1P4 receptor antagonists could be novel therapeutic agents for the treatment of influenza infection in addition to serving as a useful tool for understanding S1P4 receptor biological functions. 5-(2,5-Dichlorophenyl)-N-(2,6-dimethylphenyl)furan-2-carboxamide was identified from screening the Molecular Libraries-Small Molecule Repository (MLSMR) collection and selected as a promising S1P4 antagonist hit with moderate in vitro potency and high selectivity against the other family receptor subtypes (S1P1–3,5). Rational chemical modifications of the hit allowed the disclosure of the first reported highly selective S1P4 antagonists with low nanomolar activity and adequate physicochemical properties suitable for further lead-optimization studies.

Graphical abstractSAR analysis of a HTS-derived hit allowed the identification of the first reported potent 5-aryl furan-2-arylcarboxamide S1P receptor family subtypes (S1P1–3,5). The lead molecules (4v, 16) represent a significant pharmacological tool to explore the biological functions of the target receptor in the fundamental immunological processes.Figure optionsDownload full-size imageDownload as PowerPoint slide