Discovery, design and synthesis of novel potent and selective sphingosine-1-phosphate 4 receptor (S1P4-R) agonists

• Published in: Bioorganic & medicinal chemistry letters 2012-01, Vol.22 (1), p.537-542
• Main Authors: Guerrero, Miguel, Urbano, Mariangela, Zhao, Jian, Crisp, Melissa, Chase, Peter, Hodder, Peter, Schaeffer, Marie-Therese, Brown, Steven, Rosen, Hugh, Roberts, Edward
• Format: Article
• Language: English
• Subjects: agonists; Animals; Autoimmune diseases; Biological and medical sciences; Chemistry, Pharmaceutical - methods; Dendritic Cells - cytology; Drug Design; Humans; Immunosuppressive Agents - pharmacology; Lymphocytes - cytology; Medical sciences; Mice; Models, Chemical; Pharmacology. Drug treatments; Receptors, Lysosphingolipid - agonists; S1P4 receptor; screening; Selective small molecule S1P4-R agonists; Structure-Activity Relationship; structure-activity relationships; Thrombocytopenia; Viral infections
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.10.096

Potent and exquisitely selective agonists of the sphingosine-1-phosphate 4 receptor (S1P4-R) have been reported. The molecules herein disclosed provide novel pharmacological tools to decipher the biological function and assess the therapeutic utility of the target receptor. High affinity and selective small molecule agonists of the S1P4 receptor (S1P4-R) may have significant therapeutic utility in diverse disease areas including autoimmune diseases, viral infections and thrombocytopenia. A high-throughput screening (HTS) of the Molecular Libraries-Small Molecule Repository library identified 3-(2-(2,4-dichlorophenoxy)ethoxy)-6-methyl-2-nitropyridine as a moderately potent and selective S1P4-R hit agonist. Design, synthesis and systematic structure–activity relationships study of the HTS-derived hit led to the development of novel potent S1P4-R agonists exquisitely selective over the remaining S1P1–3,5-Rs family members. Remarkably, the molecules herein reported provide novel pharmacological tools to decipher the biological function and assess the therapeutic utility of the S1P4-R.