Identification of benzoxazole analogs as novel, S1P(3) sparing S1P(1) agonists

Bioorg Med Chem Lett. 2012 Jun 15;22(12):3973-7. doi: 10.1016/j.bmcl.2012.04.095. Epub 2012 Apr 28.

Abstract

A novel series of benzoxazole-derived S1P(1) agonists were designed based on scaffold hopping molecular design strategy combined with computational approaches. Extensive SAR studies led to the discovery of compound 17d as a selective S1P(1) agonist (over S1P(3)) with high CNS penetration and favorable DMPK properties. 17d also demonstrated in vivo pharmacological efficacy to reduce blood lymphocyte in mice after oral administration.

MeSH terms

  • Administration, Oral
  • Animals
  • Benzoxazoles / chemical synthesis*
  • Benzoxazoles / pharmacology
  • Binding Sites
  • Calcium / metabolism
  • Immunosuppressive Agents / chemical synthesis*
  • Immunosuppressive Agents / pharmacology
  • Lymphocyte Count
  • Lymphocytes / cytology
  • Lymphocytes / drug effects*
  • Mice
  • Models, Molecular
  • Protein Binding
  • Receptors, Lysosphingolipid / agonists*
  • Receptors, Lysosphingolipid / metabolism
  • Sensitivity and Specificity
  • Sphingosine-1-Phosphate Receptors
  • Structure-Activity Relationship

Substances

  • Benzoxazoles
  • Immunosuppressive Agents
  • Receptors, Lysosphingolipid
  • S1pr3 protein, mouse
  • Sphingosine-1-Phosphate Receptors
  • Calcium