Discovery, design and synthesis of novel potent and selective sphingosine-1-phosphate 4 receptor (S1P(4)-R) agonists

作者：Guerrero Miguel; Urbano Mariangela; Zhao Jian; Crisp Melissa; Chase Peter; Hodder Peter; Schaeffer Marie Therese; Brown Steven; Rosen Hugh; Roberts Edward^*

来源：Bioorganic & Medicinal Chemistry Letters, 2012, 22(1): 537-542.

DOI：10.1016/j.bmcl.2011.10.096

• S1P(4) receptor
• Selective small molecule S1P(4)-R agonists
• Autoimmune diseases
• Viral infections
• Thrombocytopenia

High affinity and selective small molecule agonists of the S1P(4) receptor (S1P(4)-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 S1P(4)-R hit agonist. Design, synthesis and systematic structure-activity relationships study of the HTS-derived hit led to the development of novel potent S1P(4)-R agonists exquisitely selective over the remaining S1P(1-3,5)-Rs family members. Remarkably, the molecules herein reported provide novel pharmacological tools to decipher the biological function and assess the therapeutic utility of the S1P(4)-R.

• 出版日期2012-1-1