Potent and Selective Agonists of Sphingosine 1-Phosphate 1 (S1P1): Discovery and SAR of a Novel Isoxazole Based Series

  • J Med Chem. 2016 Mar 24;59(6):2820-40. doi: 10.1021/acs.jmedchem.6b00089.
Scott H Watterson  1 ,  Junqing Guo  1 ,  Steve H Spergel  1 ,  Charles M Langevine  1 ,  Robert V Moquin  1 ,  Ding Ren Shen  1 ,  Melissa Yarde  1 ,  Mary Ellen Cvijic  1 ,  Dana Banas  1 ,  Richard Liu  1 ,  Suzanne J Suchard  1 ,  Kathleen Gillooly  1 ,  Tracy Taylor  1 ,  Sandra Rex-Rabe  1 ,  David J Shuster  1 ,  Kim W McIntyre  1 ,  Georgia Cornelius  1 ,  Celia D'Arienzo  1 ,  Anthony Marino  1 ,  Praveen Balimane  1 ,  Bethanne Warrack  1 ,  Luisa Salter-Cid  1 ,  Murray McKinnon  1 ,  Joel C Barrish  1 ,  Percy H Carter  1 ,  William J Pitts  1 ,  Jenny Xie  1 ,  Alaric J Dyckman  1
Affiliations
  • 1. Bristol-Myers Squibb Research and Development , P.O. Box 4000, Princeton, New Jersey 08543, United States.
PMID: 26924461 DOI: 10.1021/acs.jmedchem.6b00089
Abstract

Sphingosine 1-phosphate (S1P) is the endogenous ligand for the sphingosine 1-phosphate receptors (S1P1-5) and evokes a variety of cellular responses through their stimulation. The interaction of S1P with the S1P receptors plays a fundamental physiological role in a number of processes including vascular development and stabilization, lymphocyte migration, and proliferation. Agonism of S1P1, in particular, has been shown to play a significant role in lymphocyte trafficking from the thymus and secondary lymphoid organs, resulting in immunosuppression. This article will detail the discovery and SAR of a potent and selective series of isoxazole based full agonists of S1P1. Isoxazole 6d demonstrated impressive efficacy when administered orally in a rat model of arthritis and in a mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis.

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