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Haloallylamine inhibitors of MAO and SSAO and their therapeutic potential

  • M. G. Palfreyman
  • I. A. McDonald
  • P. Bey
  • C. Danzin
  • M. Zreika
  • G. Cremer
Part of the Journal of Neural Transmission book series (NEURAL SUPPL, volume 41)

Summary

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.

Keywords

Monoamine Oxidase Amine Oxidase SSAO Activity Monoamine Oxidase Type Suicide Substrate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • M. G. Palfreyman
    • 1
  • I. A. McDonald
    • 1
  • P. Bey
    • 1
  • C. Danzin
    • 2
  • M. Zreika
    • 2
  • G. Cremer
    • 2
  1. 1.Marion Merrell Dow Research InstituteCincinnatiUSA
  2. 2.Marion Merrell Dow Research InstituteStrasbourgFrance

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