title: Inhibition of monoamine oxidase-B by condensed pyridazines and pyrimidines: effects of lipophilicity and structure-activity relationships.
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.
authors.affiliation: Institut de Chimie, Faculté de Sciences, Université de Neuchâtel, Avenue de Bellevaux 51, CH-2000 Neuchâtel, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Altomare
authors.forename: S
authors.initials: S
authors.lastname: Cellamare
authors.forename: L
authors.initials: L
authors.lastname: Summo
authors.forename: M
authors.initials: M
authors.lastname: Catto
authors.forename: A
authors.initials: A
authors.lastname: Carotti
authors.forename: U
authors.initials: U
authors.lastname: Thull
authors.forename: P A
authors.initials: PA
authors.lastname: Carrupt
authors.forename: B
authors.initials: B
authors.lastname: Testa
authors.forename: H
authors.initials: H
authors.lastname: Stoeckli-Evans
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D018360:Crystallography, X-Ray; D066298:In Vitro Techniques; D016014:Linear Models; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D008968:Molecular Conformation; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D008996:Monoamine Oxidase Inhibitors; D011724:Pyridazines; D011743:Pyrimidines