Abstract

Studies indicate that MAO-B is induced in peripheral inflammatory diseases. To target peripheral tissues using MAO-B inhibitors that don’t permeate the BBB the MAO-B selective inhibitor deprenyl was remodeled by replacing the terminal acetylene with a CO2H function, and incorporating a para –OCH2Ar motif (compounds 10a-s). Further, in compound 32 the C-2 side chain corresponded to CH2CN. In vitro, 10c, 10j, 10k and 32 were identified as potent reversible MAO-B inhibitors, and all four compounds were more stable than deprenyl in plasma, liver microsomal and hepatocyte stability assays. In vivo, they demonstrated greater plasma bioavailability. Assessment of in vitro BBB permeability showed that compound 10k is a P-gp substrate and 10j displayed mild interaction. Importantly, compounds 10c, 10j, 10k and 32 displayed significantly reduced BBB permeability after intravenous, subcutaneous and oral administration. These polar MAO-B inhibitors are pertinent leads for evaluation of efficacy in non-CNS inflammatory disease models.