Development of Novel Monoamine Oxidase‑B (MAO-B) Inhibitors with Reduced Blood–Brain Barrier Permeability for the Potential Management of Noncentral Nervous System (CNS) Diseases

Studies
indicate that MAO-B is induced in peripheral inflammatory
diseases. To target peripheral tissues using MAO-B inhibitors that
do not permeate the blood–brain barrier (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-glycoprotein (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 noncentral nervous system (CNS)
inflammatory disease models.