New coumarin-based anti-inflammatory drug: putative antagonist of the integrins alphaLbeta2 and alphaMbeta2

J Pharm Pharmacol. 2008 Nov;60(11):1473-9. doi: 10.1211/jpp.60.11.0008.

Abstract

This study was conducted to investigate putative antagonism of integrin receptors alphaMbeta2 and alphaLbeta2 by a novel coumarin derivative (BOL-303225-A), its efficacy in-vivo after retinal ischaemia-reperfusion injury, and its bioavailability in rat plasma. A cellular adhesion assay in Jurkat and U937 cells, and a flow cytometry assay with an antibody against the beta2 subunit were conducted. BOL-303225-A bioavailability in rat plasma and the retinal levels of myeloperoxidase (MPO) after ischaemia-reperfusion injury were evaluated after oral administration (10 mg kg(-1)). In-vitro cell viability assays revealed no cytotoxicity for BOL-303225-A over a wide dose range, and IC50 values of 32.3 +/- 1.5 muM and 84.95 +/- 2.3 muM were found for Jurkat and U937 cells, respectively. The drug showed specific binding to the alphaMbeta2 and alphaLbeta2 integrin receptors expressed by U937 and Jurkat cells, respectively, producing a fluorescence shift towards lower values in a concentration-dependent manner. The pharmacokinetic profile of BOL-303225-A exhibited rapid absorption following oral administration in the rat. A significant reduction of retinal MPO levels was observed in drug-treated rats. This study demonstrated that BOL-303225-A acts as an antagonist of the integrin alphaLbeta2 and alphaMbeta2 receptors, suggesting that this drug could be used for ocular diseases such as diabetic retinopathy.

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Inflammatory Agents / administration & dosage
  • Anti-Inflammatory Agents / pharmacokinetics
  • Anti-Inflammatory Agents / pharmacology*
  • Biological Availability
  • Cell Adhesion / drug effects
  • Cell Survival / drug effects
  • Coumarins / administration & dosage
  • Coumarins / pharmacokinetics
  • Coumarins / pharmacology*
  • Dose-Response Relationship, Drug
  • Flow Cytometry
  • Humans
  • Jurkat Cells
  • Lymphocyte Function-Associated Antigen-1 / drug effects*
  • Lymphocyte Function-Associated Antigen-1 / metabolism
  • Macrophage-1 Antigen / drug effects*
  • Macrophage-1 Antigen / metabolism
  • Male
  • Peroxidase / drug effects
  • Peroxidase / metabolism
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury / drug therapy
  • Reperfusion Injury / pathology
  • Retinal Diseases / drug therapy
  • Retinal Diseases / pathology
  • U937 Cells

Substances

  • Anti-Inflammatory Agents
  • BOL-303225-A
  • Coumarins
  • Lymphocyte Function-Associated Antigen-1
  • Macrophage-1 Antigen
  • Peroxidase