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

详细信息    查看全文

• 作者：Francesco Leonetti ; Carmelida Capaldi ; Leonardo Pisani ; Orazio Nicolotti ; Giovanni Muncipinto ; Angela Stefanachi ; Saverio Cellamare ; Carla Caccia ; Angelo Carotti
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：October 4, 2007
• 年：2007
• 卷：50
• 期：20
• 页码：4909 - 4916
• 全文大小：955K
• 年卷期：v.50,no.20(October 4, 2007)
• ISSN：1520-4804

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.