Identification and synthesis of potent and selective pyridyl-isoxazole based agonists of sphingosine-1-phosphate 1 (S1P1)

  • Bioorg Med Chem Lett. 2016 May 15;26(10):2470-2474. doi: 10.1016/j.bmcl.2016.03.105.
Junqing Guo  1 Scott H Watterson  2 Steven H Spergel  2 James Kempson  2 Charles M Langevine  2 Ding Ren Shen  2 Melissa Yarde  2 Mary Ellen Cvijic  2 Dana Banas  2 Richard Liu  2 Suzanne J Suchard  2 Kathleen Gillooly  2 Tracy Taylor  2 Sandra Rex-Rabe  2 David J Shuster  2 Kim W McIntyre  2 Georgia Cornelius  2 Celia D'Arienzo  2 Anthony Marino  2 Praveen Balimane  2 Luisa Salter-Cid  2 Murray McKinnon  2 Joel C Barrish  2 Percy H Carter  2 William J Pitts  2 Jenny Xie  2 Alaric J Dyckman  2
Affiliations
  • 1. Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States. Electronic address: [email protected].
  • 2. Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-4000, United States.
Abstract

The synthesis and structure-activity relationship (SAR) of a series of pyridyl-isoxazole based agonists of S1P1 are discussed. Compound 5b provided potent in vitro activity with selectivity, had an acceptable pharmacokinetic profile, and demonstrated efficacy in a dose dependent manner when administered orally in a rodent model of arthritis.

Keywords
FTY720; Fingolimod; Isoxazole; S1P(1); Sphingosine-1-phosphate; Sphingosine-1-phosphate 1.