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Inhibition of ACAT, the enzyme which catalyses the intracellular formation of cholesteryl esters, is a very attractive target for the treatment of hypercholesterolaemia and atherosclerosis. However, in the past years many ACAT inhibitors gave disappointing results in clinical trials showing very low efficacy. In addition, their development was affected by the adrenotoxicity observed in many compounds. The discovery of two isoforms of the enzyme, namely ACAT1 and ACAT2, with different substrate specificity and different potential function, offers a precious information for planning selective inhibitors with reduced secondary effects. Today some potent, bioavailable and non adrenotoxic ACAT inhibitors are under clinical evaluation. Amongst others, a very promising compound is Avasimibe, presently in phase III clinical trials as anti-hyperlipidemic and anti-atherosclerotic agent. Finally, ACAT inhibitors have recently been proposed for the treatment of Alzheimer's disease.

A series of 2-substituted 4,5-functionalized 6-phenyl-3(2 H )-pyridazinones were synthesized and their antinociceptive activities were evaluated in the mouse abdominal constriction model. Single dose studies showed that compounds 11, 18a and 23 were more active than the reference drug, Emorfazone, in inhibiting the effects of the noxious chemical stimulus, p -phenylquinone. Subsequent dose—response studies revealed 18a to be almost seven-fold more potent than Emorfazone.

The structure of the major product from 1 and methylhydrazine is established and a mechanism for the formation of 2 involving a preliminary nucleophilic attack at the isoxazole C-5 is proposed.

A series of 6-cyano-3-phenyl-1,2,3,4-tetrahydro-1,2-diazepin-5-ones were synthesized and evaluated in vitro as antitumor agents against several human tumor cell lines. Moderate activity and differential cellular sensitivity were found for a few of the tested compounds.

4-Aminopyridazin-3(2H)-ones substituted at position 5 with a variety of oxygenated carbon chains were obtained in good yields by reductive opening of the pentatomic ring of isoxazolo[3,4-d]pyridazinones (1). Starting from ethyl 4-acylisoxazole-3-carboxylates, several 4,5-functionalized 3(2H)pyridazinones (3) are obtained in a one step by treatment with the appropriate hydrazine and Pd/C

The title compound 2 was found to be a very useful intermediate to synthesize five- and six-membered hetero-condensed pyridazinones in high yields under generally mild and simple reaction conditions

A series of 2-substituted 4,5-functionalized 6-phenyl-3(2 H )-pyridazinones were synthesized and their antinociceptive activities were evaluated in the mouse abdominal constriction model. Single dose studies showed that compounds 11, 18a and 23 were more active than the reference drug, Emorfazone, in inhibiting the effects of the noxious chemical stimulus, p -phenylquinone. Subsequent dose—response studies revealed 18a to be almost seven-fold more potent than Emorfazone.

A series of 4,5-functionalized-2-methyl-6-(substituted phenyl)-3 (2H)-pyridazinones were synthesized and evaluated as platelet aggregation inhibitors in human platelet rich plasma (PRP). The new products generally displayed significant higher activity with respect to the corresponding unsubstituted aryl compounds. Compounds 27 and 31 appeared of particular interest, being their IC50s in the submicromolar range. Structure-activity relationships (SARs) are discussed.

The title compound 2 was found to be a very useful intermediate to synthesize five- and six-membered hetero-condensed pyridazinones in high yields under generally mild and simple reaction conditions

A series of substituted indenopyridazinones (4b-h) has been synthesized and tested for their antisecretory and antiulcer activity, in comparison with ranitidine, as reference drug. While the monomethoxy (4b-d), as well as the benzyloxy (4f) and the 6,9-dimethoxy (4g) derivatives were found to be devoid of overt antisecretory properties, the 9-methoxy (4e) was weakly active. The most interesting compound of this class was the 7,8-dimethoxy substituted (4h), which at an oral dose of 30 mg/kg still retains a significant activity. The dihydroderivatives of 4g,h (compounds 1g,h) were more active (1g) or comparable (1h) to the parent compounds, thus proving that the 4, 4a-double bond, which was an essential requirement in the analogues 2 and 3, is not necessary in this new series. The disubstituted derivatives (1g,h; 4g,h) were also tested as antiulcer agents, in two different models. All compounds were able to prevent haemorragic lesions induced in rats by 90% ethanol in a dose dependent manner. In the indomethacin model they still showed a significant activity, though lower than in the previous test. Attempts have been made to elucidate their mechanism of action.

A series of 4,5-functionalized-2-methyl-6-(substituted phenyl)-3 (2H)-pyridazinones were synthesized and evaluated as platelet aggregation inhibitors in human platelet rich plasma (PRP). The new products generally displayed significant higher activity with respect to the corresponding unsubstituted aryl compounds. Compounds 27 and 31 appeared of particular interest, being their IC50s in the submicromolar range. Structure-activity relationships (SARs) are discussed.

A series of 5-acyl-6-phenyl-2,4-substituted-3(2H)-pyridazinones and analogous benzo[h]cinnolin-3,5-diones with reduced flexibility has been prepared and evaluated as human platelet aggregation inhibitors. The 4-methylsulfoxide 13b was the most potent compound of the series (IC50 = 1.2 microM). SAR studies have shown the primary importance of an electronegative substituent at position 4 and an acetyl group at position 5 of the pyridazine system for potent platelet aggregation inhibitory activity. Biological tests performed on a group of representative compounds showed these products have not effects on prostaglandins, thromboxanes and nitric oxide biosynthetic pathways. Some of synthesized compounds produced a moderate increase of cAMP level in platets which does not depend on the adenylate-cyclase stimulation. Tests performed on human platelet PDE III have shown that these compounds are not inhibitors of this enzyme.

A series of twenty pyridazinyl-styrilketones, substituted at position 4 with linear or cyclic tertiary amino groups, were synthesized and evaluated in vitro as antitumor agents against 60 human tumor cell-lines. Moderate activity and differential cell sensitivity were found for several of the compounds. Cell-line XF-498L (panel:Brain) showed differential cell sensitivity towards compound 5b (more than 1000 times the mean sensitivity of all cell-lines).

A series of 6-cyano-3-phenyl-1,2,3,4-tetrahydro-1,2-diazepin-5-ones were synthesized and evaluated in vitro as antitumor agents against several human tumor cell lines. Moderate activity and differential cellular sensitivity were found for a few of the tested compounds.

The structure of the major product from 1 and methylhydrazine is established and a mechanism for the formation of 2 involving a preliminary nucleophilic attack at the isoxazole C-5 is proposed.

4-Aminopyridazin-3(2H)-ones substituted at position 5 with a variety of oxygenated carbon chains were obtained in good yields by reductive opening of the pentatomic ring of isoxazolo[3,4-d]pyridazinones (1). Starting from ethyl 4-acylisoxazole-3-carboxylates, several 4,5-functionalized 3(2H)pyridazinones (3) are obtained in a one step by treatment with the appropriate hydrazine and Pd/C