Inhibition of monoamine oxidase types A and B by 2-aryl-4H-1,3,4-oxadiazin-5(6H)-ones derivatives

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.

Section: Resultssupporting

confidence: 86%

Inhibition of Monoamine Oxidase-B by Condensed Pyridazines and Pyrimidines: Effects of Lipophilicity and Structure−Activity Relationships

Altomare

Cellamare²,

Summo³

et al. 1998

“…Monosubstitution in position 3 usually led to more active or equipotent compounds (7,(12)(13)(14)(15)(16)(17). Irrespective of the 4-substituent, a 3-phenyl substituent was highly favorable to activity (7,(9)(10)(11). A surprising result, however, is the poor activity of compound 8 (3-phenyl-4-methyl-IP), since the absence of a 4-substituent or a 4-substituent larger than methyl (benzyl, benzoyl, ethoxycarbonyl; 9-11) increases activity relative to compound 8. It is also interesting to note that a heterocycle in position 3 is unfavorable to activity (18)(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Monoamine Oxidase-B by 5H-Indeno[1,2-c]pyridazines: Biological Activities, Quantitative Structure-Activity Relationships (QSARs) and 3D-QSARs

Kneubühler¹,

Thull²,

Altomare³

et al. 1995

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).

“…The decrease in activity of compounds bearing a substituted arylmethoxy fragment could be due to steric hindrance if a hydrophobic interaction exists between the arylmethoxy group of these tetrazole derivatives and a putative hydrophobic pocket of the enzyme active site, as we have previously proposed for analogous compounds. [24][25][26] Thus, the hydrophobic character of the phenylmethoxy group seems to be important for the increase of the activity and selectivity toward MAO B. The adjunction of a flexible CH2O bridge between the two phenyls dramatically increased the activity and selectivity of the inhibitors 16a and 18a compared to 15e and 17e.…”

Section: Resultsmentioning

confidence: 99%

“…23 Another new promising class of reversible MAO B inhibitors structurally related to a cyclic hydrazone moiety 8 was studied in our laboratory as described in recent papers on the activities of l,3,4-oxadiazol-2(3if)one derivatives 924•25 and of 4ff-l,3,4-oxadiazin-3(6fl> one derivatives 10. 26 The 5-[4-(phenylmethoxy)phenyl]-3-(2-cyanoethyl)-l,3,4-oxadiazol-2(3if)-one (11a), its analogue the oxadiazolethione lib, and the 5-[4-(phenylmethoxy)phenyl]-3-(2-hydroxyethyl)-l,3,4-oxadiazol-2(3if)-one (11c) were shown to act as reversible, highly potent, and selective MAO B inhibitors. Their IC50 (MAO B) values were in the low nanomolar range of 1.4-4.6 nM and their selectivities, estimated from the ICso(MAO A)/ICso(MAO B) ratio, were from 3200 to >71 000.…”

Section: Introductionmentioning

confidence: 99%

Selective and Potent Monoamine Oxidase Type B Inhibitors: 2-Substituted 5-Aryltetrazoles Derivatives

Lebreton

Curet²,

Gueddari³

et al. 1995

Self Cite

Twenty new 2-(cyanoalkyl)tetrazoles (15 and 16) and twenty new 2-(hydroxyalkyl)tetrazoles (17 and 18) were synthesized and investigated in vitro for their abilities to inhibit selectively rat brain monoamine oxidase (MAO) B over MAO A. Most of them were MAO B inhibitors and those bearing a substituted 4-(arylmethoxy)phenyl group in the position 5 of the tetrazole ring had IC50 values between 8 microM for 18d and 2 nM for 16a (30 nM for lazabemide) with a selectivity toward MAO B of 37,000 for 16a. The reversibility of their inhibitory activity was demonstrated by in vitro dialysis tests. The 5-[4-(phenylmethoxy)phenyl]-2-(2-cyanoethyl)tetrazole (16a) its derivative 16h and the 5-[4-(phenylmethoxy)phenyl]-2-(2-hydroxyethyl)tetrazole (18a) and its derivative 18h were found to be potent, in vitro selective, and competitive MAO B inhibitors. Tetrazole 16a can be considered one of the most active and selective competitive MAO B inhibitors known up to now. This compound was selected for ex vivo experiments and was shown to be a strong and reversible MAO B inhibitor with a short duration of action after oral administration at 5 mg/kg. The structure-activity approach gives rise to the great importance of lipophilicity over electronic effects of the compounds in these series.