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Inhibition of monoamine oxidase-B by 5H-indeno[1,2-c]pyridazines: biological activities, quantitative structure-activity relationships (QSARs) and 3D-QSARs

Kneubuhler, S.
Thull, Ulrike
Altomare, Cosimo
Carta, V.
Gaillard, Patrick
Carotti, Angelo
Testa, Bernard
Published in Journal of Medicinal Chemistry. 1995, vol. 38, no. 19, p. 3874-3883
Abstract A large series (66 compounds) of indeno[1,2-c]pyridazin-5-ones (IPs) were synthesized and tested on their monoamine oxidase-A (MAO-A) and MAO-B inhibitory activity. All of the tested compounds acted preferentially on MAO-B displaying weak (nonmeasurable IC50 values) to high (submicromolar IC50 values) activities. The most active compound was p-CF3-3-phenyl-IP (IC50 = 90 nM). Multiple linear regression analysis of the substituted 3-phenyl-IPs yielded good statistical results (q2 = 0.74; r2 = 0.86) and showed the importance of lipophilic, electronic, and steric properties of the substituents in determining inhibitory potency. Various comparative molecular field analysis studies were performed with different alignments and including the molecular lipophilicity potential. This led to a model including the steric, electrostatic and lipophilicity fields and having a good predictive value (q2 = 0.75; r2 = 0.93).
Keywords Computer GraphicsMagnetic Resonance SpectroscopyModels, MolecularMolecular ConformationMonoamine Oxidase/metabolismMonoamine Oxidase Inhibitors/*chemistry/*pharmacologyPyridazines/chemical synthesis/*chemistry/*pharmacologySpectrum AnalysisStructure-Activity Relationship
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PMID: 7562919

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Deposited on : 2010-08-06

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