- ALPHA-AMINOAMIDE DERIVATIVES USEFUL IN THE TREATMENT OF PSYCHIATRIC DISORDERS
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The disclosure relates to pharmacotherapy of a psychiatric disorder which is schizophrenia and/or anxiety, wherein schizophrenia includes schizophrenia related disorders such as brief psychotic disorders, delusional disorders, schizoaffective disorders, a
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- PROCESS FOR THE PRODUCTION OF 2-[4-(3- OR 2-FLUOROBENZYLOXY)BENZYLAMINO]PROPANAMIDES WITH HIGH PURITY DEGREE
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A process for obtaining therapeutically active 2-[4-(3- and 2-(flurobenzyloxy)benzylamino]propanamides, and their salts with pharmaceutically acceptable acids with high purity degree, in particular, with a content of dibenzyl derivatives impurities lower
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Page/Page column 71
(2009/07/17)
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- Solid-phase synthesis and insights into structure-activity relationships of safinamide analogues as potent and selective inhibitors of type B monoamine oxidase
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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 (IC 50 = 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 α-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 α-aminoamide enantiomers, including the two rigid analogues (21) of safinamide, indicated likely enantioselective interactions at the enzymatic binding sites.
- Leonetti, Francesco,Capaldi, Carmelida,Pisani, Leonardo,Nicolotti, Orazio,Muncipinto, Giovanni,Stefanachi, Angela,Cellamare, Saverio,Caccia, Carla,Carotti, Angelo
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p. 4909 - 4916
(2008/02/13)
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