Solid-Phase Synthesis and Insights into Structure−Activity Relationships of Safinamide Analogues as Potent and Selective Inhibitors of Type B Monoamine Oxidase

Abstract

Safinamide, (S)-N2-{4-[(3-fluorobenzyl)oxy]benzyl}alaninamide methanesulfonate, which is in phase III clinical trials as an anti-Parkinson drug, and a library of alkanamidic analogues were prepared through an expeditious solid-phase synthesis and evaluated for their monoamine oxidase B (MAO-B) and monoamine oxidase 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-affinity relationships and docking simulations pointed out strong negative steric effects of alpha-aminoamide side chains and 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 alpha-aminoamide enantiomers, including the two rigid analogues (21) of safinamide, indicated likely enantioselective interactions at the enzymatic binding sites.

Multiphoton fluorescence lifetime imaging microscopy reveals free-to-bound NADH ratio changes associated with metabolic inhibition

“…36 4-CMBC is used as an early building block in the solid-phase synthesis of the tyrosine kinase inhibitor Imatinib (Gleevec). 37 It has been discussed in a 2010 paper as an experimental Wingless-Int (WNT) pathway inhibitor, 38 and data to that effect were published in a PhD thesis in 2011. 39 However, to our knowledge, no peer-reviewed source confirms that mechanism or any other although it is employed as an initiator of atom transfer radical polymerization in polymer chemistry.…”

A combined theoretical and experimental study on the structure, vibrational, and electronic properties of antiparkinsonian drug safinamide

“…These results would indicate the high stability of the salt in solution and, probably, its high activity as inhibitor of MAO-B [23,24], due to the extended conformation with the 3-fluorobenzyloxy moiety and the primary amide group oriented towards the flavin cofactor [23]. Notably, diverse electronic and hydrophobic properties of mesylate salt due to the fluorobenzyloxy group may suggest an important steric effect as the most likely cause of the observed increase in affinity [24].…”

Coumarin: A Natural, Privileged and Versatile Scaffold for Bioactive Compounds

“…Safinamide and its analogues were tested for their rMAO inhibitory activity and selectivity. Interestingly, two derivatives, ( S )-3-chlorobenzyloxyalaninamide and ( S )-3-chlorobenzyloxyserinamide, resulted in more potent MAO B inhibitors than safinamide (IC 50 33 and 43 nM, respectively, vs. 98 nM) but with a lower MAO B selectivity index (SI 3455 and 1967, respectively, vs. 5918) [ 111 ].…”