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

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

Affiliation

  • 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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