Haloallylamine inhibitors of MAO and SSAO and their therapeutic potential
Based on mechanistic understandings, molecular modeling and extensive quantitative structure-activity relationships, appropriately substituted haloallylamine derivatives were designed as potential mechanism-based inhibitors of MAO and/or SSAO. Potent inhibition of MAO-B and SSAO occurred with fluoroallylamines whereas chloroallylamines, such as MDL 72274A ((E)-2-phenyl-3-chloroallylamine hydrochloride), were selective and potent inhibitors of SSAO. MDL 72974A (E)-2-(4-fluoroph-enethyl)-3-fluoroallylamine hydrochloride is a potent (IC50 = 10-9M) inhibitor of both MAO-B and SSAO, with 190-fold lower affinity for MAO-A. In clinical studies, oral doses as low as 100μg produced substantial inhibition of platelet MAO-B. Essentially complete inhibition occurred at 1 mg with the effect lasting 6–10 days. One or 4 mg MDL 72974A given daily for 28 days to 40 Parkinson’s patients treated with L-dopa produced statistically significant reductions in the Unified Parkinson’s Disease Rating Scale. MAO-B inhibitors, such as MDL 72974A and L-deprenyl, offer the potential of being neuroprotective in Parkinson’s Disease and other neurogenerative disorders. Concommitant inhibition of SSAO may provide additional, but as yet unproven, advantages over pure inhibitors of MAO-B.
KeywordsMonoamine Oxidase Amine Oxidase SSAO Activity Monoamine Oxidase Type Suicide Substrate
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