Statin-derived 1,3-oxazinan-2-ones as submicromolar inhibitors of LFA-1/ICAM-1 interaction: stabilization of the metabolically labile vanillyl side chain

Bioorg Med Chem Lett. 2004 May 17;14(10):2483-7. doi: 10.1016/j.bmcl.2004.03.006.

Abstract

Modification of the vanillyl substituent on a potent, semisynthetic lymphocyte function-associated antigen (LFA)-1/intercellular adhesion molecule (ICAM)-1 binding inhibitor of the statin family resulted in metabolically more stable analogues that displayed submicromolar inhibitory activity in vitro and considerable anti-inflammatory activity in vivo. The benzodioxole derivative 2b emerged with the best overall profile.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / chemical synthesis*
  • Anti-Inflammatory Agents / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Stability
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / chemical synthesis*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Inflammation / drug therapy
  • Inhibitory Concentration 50
  • Intercellular Adhesion Molecule-1 / drug effects
  • Intercellular Adhesion Molecule-1 / metabolism*
  • Lovastatin
  • Lymphocyte Function-Associated Antigen-1 / drug effects
  • Lymphocyte Function-Associated Antigen-1 / metabolism*
  • Microsomes, Liver
  • Protein Binding / drug effects
  • Rats
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Lymphocyte Function-Associated Antigen-1
  • Intercellular Adhesion Molecule-1
  • Lovastatin