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

Altomare, Cosimo; Cellamare, S.; Summo, L.; Catto, M.; Carotti, Angelo; Thull, Ulrike; Carrupt, Pierre-Alain; Testa, Bernard; Stoeckli-Evans, H.

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Title		Inhibition of monoamine oxidase-B by condensed pyridazines and pyrimidines: Effects of lipophilicity and structure-activity relationships
Authors		Altomare, Cosimo Cellamare, S. Summo, L. Catto, M. Carotti, Angelo Thull, Ulrike Carrupt, Pierre-Alain Testa, Bernard Stoeckli-Evans, H. show all authors [1 - 9]
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
Full text		Article - Limited access to UNIGE Other version: http://pubs.acs.org/doi/pdf/10.1021/jm981005y
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. https://archive-ouverte.unige.ch/unige:10532