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. Epub 2016 Apr 1.

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.

MeSH terms

  • Administration, Oral
  • Animals
  • Arthritis, Experimental / drug therapy*
  • Chemistry Techniques, Synthetic
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical / methods
  • Humans
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology
  • Lymphocyte Count
  • Lysophospholipids / agonists*
  • Male
  • Rats, Inbred Lew
  • Receptors, Lysosphingolipid / agonists
  • Sphingosine / agonists
  • Sphingosine / analogs & derivatives*
  • Structure-Activity Relationship*

Substances

  • Isoxazoles
  • Lysophospholipids
  • Receptors, Lysosphingolipid
  • sphingosine 1-phosphate
  • Sphingosine