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-fluorophenethyl)-3-fluoroallylamine hydrochloride is a potent (IC50 = 10(-9) M) inhibitor of both MAO-B and SSAO, with 190-fold lower affinity for MAO-A. In clinical studies, oral doses as low as 100 micrograms 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.
Palfreyman
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MG
Marion Merrell Dow Research Institute, Cincinnati, Ohio.
McDonald
I A
IA
Bey
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P
Danzin
C
C
Zreika
M
M
Cremer
G
G
D000498:Allyl Compounds / Q000627:therapeutic use*; D006631:Amine Oxidase (Copper-Containing); D000818:Animals; D002082:Butylamines / Q000627:therapeutic use*; D004341:Drug Evaluation; D006801:Humans; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000627:therapeutic use*; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors*; D010300:Parkinson Disease / Q000188:drug therapy*; D011437:Propylamines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012663:Semicarbazides / Q000494:pharmacology*
D000498:Allyl Compounds; D002082:Butylamines; C090015:MDL 72274A; D008996:Monoamine Oxidase Inhibitors; D011437:Propylamines; D012663:Semicarbazides; C058000:mofegiline; C010059:carbamylhydrazine; D006631:Amine Oxidase (Copper-Containing); D000587:Oxidoreductases Acting on CH-NH Group Donors