HALOALLYLAMINE INHIBITORS OF MAO AND SSAO AND THEIR THERAPEUTIC POTENTIAL

Based on mechanistic understandings, molecular modeling and extensive quantitative structure-activity relationships, appropriately substitut ed haloallylamine derivatives were designed as potential mechanism-bas ed 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 selectiv e and potent inhibitors of SSAO. MDL 72974A (E)-2(4-fluorophenethyl)-3 -fluoroallylamine hydrochloride is a potent (IC50 = 10(-9) M) inhibito r of both MAO-B and SSAO, with 190-fold lower affinity for MAO-A. In c linical studies, oral doses as low as 100 mu g produced substantial in hibition of platelet MAO-B. Essentially complete inhibition occurred a t 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 prod uced statistically significant reductions in the Unified Parkinson's D isease Rating Scale. MAO-B inhibitors, such as MDL 72974A and L-depren yl, offer the potential of being neuroprotective in Parkinson's Diseas e and other neurogenerative disorders. Concommitant inhibition of SSAO may provide additional, but as yet unproven, advantages over pure inh ibitors of MAO-B.