Fused tricyclic indoles as S1P₁ agonists with robust efficacy in animal models of autoimmune disease

Bioorg Med Chem Lett. 2012 Jul 1;22(13):4404-9. doi: 10.1016/j.bmcl.2012.04.129. Epub 2012 May 7.

Abstract

Two series of fused tricyclic indoles were identified as potent and selective S1P(1) agonists. In vivo these agonists produced a significant reduction in circulating lymphocytes which translated into robust efficacy in several rodent models of autoimmune disease. Importantly, these agonists were devoid of any activity at the S1P(3) receptor in vitro, and correspondingly did not produce S1P(3) mediated bradycardia in telemeterized rat.

MeSH terms

  • Animals
  • Autoimmune Diseases / drug therapy
  • Disease Models, Animal
  • Female
  • Humans
  • Immunologic Factors / chemistry*
  • Immunologic Factors / pharmacokinetics
  • Immunologic Factors / therapeutic use
  • Indoles / chemistry*
  • Indoles / pharmacokinetics
  • Indoles / therapeutic use
  • Lymphocytes / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microsomes / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Lysosphingolipid / agonists*
  • Receptors, Lysosphingolipid / metabolism
  • Structure-Activity Relationship

Substances

  • Immunologic Factors
  • Indoles
  • Receptors, Lysosphingolipid