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.