New coumarin-based anti-inflammatory drug: putative antagonist of the integrins αLβ2 and αMβ2

Abstract

This study was conducted to investigate putative antagonism of integrin receptors αMβ2 and αLβ2 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 β2 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 μM and 84.95 ± 2.3 μM were found for Jurkat and U937 cells, respectively. The drug showed specific binding to the αMβ2 and αLβ2 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 αLβ2 and αMβ2 receptors, suggesting that this drug could be used for ocular diseases such as diabetic retinopathy.