Sphingosine-1-phosphate (S1P) is the endogenous ligand for the sphingosine-1-phosphate family of G-protein coupled receptors (S1P1-5). The interaction of S1P with the S1P receptors plays a fundamental physiological role in a number of processes including proliferation, angiogenesis, cytoskeletal rearrangement, vascular development, and lymphocyte trafficking. Agonism at S1P1, in particular, is immunomodulatory via a unique mechanism involving impaired lymphocyte egress from the thymus and secondary lymphoid organs.  Clinical validation of S1P receptor modulation therapy was recently achieved with the approval of fingolimod (FTY720), the phosphorylated metabolite of which is a non-selective S1P receptor agonist, as the first oral disease modifying treatment for relapsing remitting multiple sclerosis.  This presentation will detail the discovery and SAR of a potent and selective series of pyrazole based agonists of S1P1. Compounds in this series were highly active in a pharmacodynamic model (suppression of circulating lymphocytes) and demonstrated impressive efficacy when administered orally in rodent models of arthritis and multiple sclerosis.

Identification of potent and selective pyrazole based agonists of sphingosine-1-phosphate 1 (S1P1)

244th National Meeting (2012)

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