Inhibition of monoamine oxidase-B by condensed pyridazines and pyrimidines: effects of lipophilicity and structure-activity relationships

J Med Chem. 1998 Sep 24;41(20):3812-20. doi: 10.1021/jm981005y.


A number of condensed pyridazines and pyrimidines were synthesized and tested for their monoamine oxidase-A (MAO-A) and MAO-B inhibitory activity. Their lipophilicity was examined by measuring partition coefficients and RP-HPLC capacity factors, revealing some peculiar electronic and conformational effects. Further insights were obtained by X-ray crystallography and a thermodynamic study of RP-HPLC retention. Structure-activity relations highlighted the main factors determining both selectivity and inhibitory potency. Thus, while most of the condensed pyridazines were reversible inhibitors of MAO-B with little or no MAO-A effects, the pyrimidine derivatives proved to be reversible and selective MAO-A inhibitors. Substituents on the diazine nucleus modulated enzyme inhibition. A QSAR analysis of X-substituted 3-X-phenyl-5H-indeno[1,2-c]pyridazin-5-ones showed lipophilicity to increase MAO-B and not MAO-A inhibitory activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / enzymology
  • Brain / ultrastructure
  • Crystallography, X-Ray
  • In Vitro Techniques
  • Linear Models
  • Mitochondria / drug effects
  • Mitochondria / enzymology
  • Models, Molecular
  • Molecular Conformation
  • Monoamine Oxidase Inhibitors* / chemical synthesis
  • Monoamine Oxidase Inhibitors* / chemistry
  • Monoamine Oxidase Inhibitors* / pharmacology
  • Pyridazines* / chemical synthesis
  • Pyridazines* / chemistry
  • Pyridazines* / pharmacology
  • Pyrimidines* / chemical synthesis
  • Pyrimidines* / chemistry
  • Pyrimidines* / pharmacology
  • Rats
  • Structure-Activity Relationship


  • Monoamine Oxidase Inhibitors
  • Pyridazines
  • Pyrimidines