文摘
Safinamide, (S)-N2-{4-[(3-fluorobenzyl)oxy]benzyl}alaninamide methanesulfonate, which is in phase IIIclinical trials as an anti-Parkinson drug, and a library of alkanamidic analogues were prepared through anexpeditious solid-phase synthesis and evaluated for their monoamine oxidase B (MAO-B) and monoamineoxidase A (MAO-A) inhibitory activity and selectivity. (S)-3-Chlorobenzyloxyalaninamide (8) and (S)-3-chlorobenzyloxyserinamide (13) derivatives proved to be more potent MAO-B inhibitors than safinamide(IC50 = 33 and 43 nM, respectively, vs 98 nM) but with a lower MAO-B selectivity (SI = 3455 and 1967,respectively, vs 5918). The highest MAO-B inhibitory potency (IC50 = 17 nM) and a good selectivity (SI= 2941) were displayed by (R)-21, a tetrahydroisoquinoline analogue of safinamide. Structure-affinityrelationships and docking simulations pointed out strong negative steric effects of -aminoamide side chainsand para substituents of the benzyloxy groups and favorable hydrophobic interactions of meta substituents.The significantly diverse MAO-B affinities of a number of R and S -aminoamide enantiomers, includingthe two rigid analogues (21) of safinamide, indicated likely enantioselective interactions at the enzymaticbinding sites.
