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Inhibition of monoamine oxidase-B by condensed pyridazines and pyrimidines: Effects of lipophilicity and structure-activity relationships |
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Published in | Journal of medicinal chemistry. 1998, vol. 41, no. 20, p. 3812-3820 | |
Abstract | 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 | |
Keywords | Animals — Brain/drug effects/enzymology/ultrastructure — Crystallography, X-Ray — Linear Models — Mitochondria/drug effects/enzymology — Models, Molecular — Molecular Conformation — Monoamine Oxidase Inhibitors/chemical synthesis/chemistry/pharmacology — Pyridazines/chemical synthesis/chemistry/pharmacology — Pyrimidines/chemical synthesis/chemistry/pharmacology — Rats — Structure-Activity Relationship | |
Identifiers | DOI: 10.1021/jm981005y PMID: 9748356 | |
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Citation (ISO format) | ALTOMARE, Cosimo et al. Inhibition of monoamine oxidase-B by condensed pyridazines and pyrimidines: Effects of lipophilicity and structure-activity relationships. In: Journal of medicinal chemistry, 1998, vol. 41, n° 20, p. 3812-3820. doi: 10.1021/jm981005y https://archive-ouverte.unige.ch/unige:10532 |