Characterisation of furoxancarbonitriles as a new class of vasodilators.

The synthesis, structural characterization, NO-donor properties, and in vitro vasodilating activities of a series of furoxancarbonitriles 2, 17-22a, b are reported. Some derivatives (2b, 2a, 18b, 21b, 22b) are more potent vasodilating agents than sodium nitroprusside (SNP), the reference compound, some others display similar potency (17b, 19b, 20b). Log EC50 values fit well on the linear correlation log EC50 versus log C0.1(1 min) (namely the logarithm of the concentration able to release 2.6 mumol l-1 min-1 of NO) found in a previous work. The haemodynamic profile in anaesthetised pigs for some selected derivatives (2a, b, 19a, b) is also presented. These profiles are consistent with that known for another furoxan NO-donor (4-hydroxymethyl-3-furoxancarboxamide, CAS 1609) and suggest similar characteristic of in vivo NO-release.

New 1,4-dihydropyridines conjugated to furoxanyl moieties, endowed with both nitric oxide-like and calcium channel antagonist vasodilator activities.

A series of 4-phenyl-1,4-dihydropyridines substituted at the ortho and meta positions of the phenyl ring with NO-donating furoxan moieties and their non-NO-releasing furazan analogues were synthesized and pharmacologically characterized. The vasodilator activities of these compounds were evaluated on rat aorta and expressed as EC50 values or as EC50iGC values when obtained in the presence of inhibitors of guanylate cyclase methylene blue (MB) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Affinities to 1, 4-DHP receptors on Ca2+ channels, expressed as IC50 values, were determined through displacement experiments of [3H]nitrendipine on rat cortex homogenates. A linear correlation between IC50 and EC50 values was found for compounds unable to release NO. EC50calcd values for derivatives containing NO-donor moieties, expression of the Ca2+-blocking component of their vasodilator activity, were interpolated on this linear regression. They showed a good correspondence with EC50iGC values determined in the presence of soluble guanylate cyclase inhibitors. Analysis of EC50iGC/EC50 ratios provided a useful tool to distinguish well-balanced hybrids from derivatives biased toward Ca2+-blocking or NO-dependent vasodilator activity. A detrimental effect on affinity to the 1, 4-DHP receptor, due to substitution at the ortho and meta positions of the 4-phenyl ring, was observed. SAR to explain this effect is proposed.

A new class of furoxan derivatives as NO donors: mechanism of action and biological activity.

1. The mechanism of action and biological activity of a series of R-substituted and di-R-substituted phenylfuroxans is reported. 2. Maximal potency as vasodilators on rabbit aortic rings, precontracted with noradrenaline (1 microM), was shown by phenyl-cyano isomers and by the 3,4-dicyanofuroxan, characterized by a potency ratio 3-10 fold higher than glyceryl trinitrate (GTN). This effect was reduced upon coincubation with methylene blue or oxyhaemoglobin (10 microM). 3. The furoxan derivatives showing maximal potency as vasodilators were also able to inhibit collagen-induced platelet aggregation, with IC50 values in the sub-micromolar range. 4. The furoxan derivatives were able to stimulate partially purified, rat lung soluble guanylate cyclase; among the most active compounds, the 3-R-substituted isomers displayed a higher level of stimulatory effect than the 4-R analogues. 5. Solutions (0.1 mM) of all the tested furoxans, prepared using 50 mM phosphate buffer, pH 7.4, (diluting 10 mM DMSO stock solutions) did not release nitric oxide (NO) spontaneously; however in presence of 5 mM L-cysteine, a significant NO-releasing capacity was observed, which correlated significantly with their stimulation of the guanylate cyclase activity.

Pharmacochemistry of the furoxan ring: recent developments.

In the present work recent results obtained in the pharmacochemistry of the furoxan system are reported. In particular, after a brief description of the salient points of the furoxan chemistry, the synthesis and the properties of a series of Nifedipine and Prazosin analogues, containing this heterocyclic system, are described. Since we observed that a few furoxan derivatives are able to elicit both a dose-dependent rise in platelet cGMP levels and to promote a dose-dependent inhibition of AA-induced [Ca++] rise, and that many substituted furoxans show potent vasodilating and antiaggregatory activity, the possibility of using the furoxan system as a lead in the design of new vasodilators is also discussed.

Synthesis and H2-antagonist properties of some 1,2,5-thiadiazole-1-oxide derivatives.

A series of 1,2,5-thiadiazole-1-oxide derivatives has been synthesized and studied for its H2-antagonist properties. These derivatives can be considered derived from classical H2-antagonists in which the structure was deeply modified in order to evidence the minimal structural requirements for the activity. It was found that it is sufficient to have the 1,2,5-thiadiazole-1-oxide ring substituted with an alkylamino moiety and with an aliphatic chain linked to the hydroxy or ether group to achieve compounds as active as cimetidine. A few considerations on the binding on guinea-pig cerebral cortex of a series of H2-antagonists with more and more simplified structures are also reported.

Synthesis and cardiovascular properties of furazanyl-1,4-dihydropyridines and of furoxanyl analogues.

A series of furazanyl- and furoxanyl-1,4-dihydropyridines has been synthesized and tested for their cardiovascular activity. The new compounds showed a modest activity in comparison with nifedipine and some selectivity for the myocardial muscle. The most active compound was diethyl 1,4-dihydro-2,6-dimethyl-4-(3-phenyl-4-furoxanyl)-3,5-pyridine dicarboxylate, 4d.