This work is aimed at the synthesis and pharmacological evaluation of COX-2 inhibitors endowed with NO-donor properties. Nitric oxide is an important physiological messenger which regulates diverse functions. In particular, in the cardiovascular system it plays important roles in maintaining the micro and the macrovascular homeostasis through a number of mechanisms including vasodilation, modulation of monocyte and platelet adhesion, inhibition of platelet aggregation and inhibition of the smooth muscle cell proliferation. In the light of the picture outlined above, NO-donor COX-2 inhibitors could benefit from reduced cardiotoxicity with respect to the classical ones, as supplying exogenous NO could balance the impairment of prostacyclin production. As a template for the design of new ligands, the diarylheterocyclic structure of the most important coxibs, among which Celecoxib, Rofecoxib, Valdecoxib, was chosen. The bis(phenyl)substituted pentatomic heterocycle present in the reference compounds, respectively pyrazole, furan-2-one and isoxazole, was replaced by a bis(phenyl)substituted 1,2,5-oxadiazole 2-oxide (furoxan). Until then the furoxan nucleus, known for its NO-donor properties, had never been used as a scaffold for the design of selective COX-2 inhibitors. One of the two phenyl groups bears at the 4-position either an aminosulfonyl (as in Celecoxib) or a methylsulfonyl (as in Rofecoxib and Valdecoxib), as the sulfonyl groups are known to be one of the determinants of COX-2 selectivity. The furazan analogues, deprived of the ability to release NO, were also considered for comparison purposes. Encouraged by the results achieved with this series of compounds, we decided to pursue the same concept of symbiotic drug with a different approach. While in the first case the COX-2 inhibitory pharmacophore and the NO-releasing moiety coincided, as the 1,2,5-oxadiazole N-oxide ring constituted the pentatomic core of the diarylheterocyclic structure, in our new project the two pharmacophores are distinct, with the NO-donor portion included as a substituent of the diarylheterocyclic scaffold. As a lead structure the imidazolic compound UR-8880, developed by Uriach group, was chosen, whose 4-methoxy group was replaced by nitrooxyalkyloxy chains of different length. All synthesised products were characterised from a structural point of view, the COX inhibition profile was studied in vitro and the binding mode was investigated through molecular modelling techniques.
Design of new diarylheterocycles endowed with COX-2 inhibitory and NO-dependent activities
TOSCO, Paolo
2006-01-01
Abstract
This work is aimed at the synthesis and pharmacological evaluation of COX-2 inhibitors endowed with NO-donor properties. Nitric oxide is an important physiological messenger which regulates diverse functions. In particular, in the cardiovascular system it plays important roles in maintaining the micro and the macrovascular homeostasis through a number of mechanisms including vasodilation, modulation of monocyte and platelet adhesion, inhibition of platelet aggregation and inhibition of the smooth muscle cell proliferation. In the light of the picture outlined above, NO-donor COX-2 inhibitors could benefit from reduced cardiotoxicity with respect to the classical ones, as supplying exogenous NO could balance the impairment of prostacyclin production. As a template for the design of new ligands, the diarylheterocyclic structure of the most important coxibs, among which Celecoxib, Rofecoxib, Valdecoxib, was chosen. The bis(phenyl)substituted pentatomic heterocycle present in the reference compounds, respectively pyrazole, furan-2-one and isoxazole, was replaced by a bis(phenyl)substituted 1,2,5-oxadiazole 2-oxide (furoxan). Until then the furoxan nucleus, known for its NO-donor properties, had never been used as a scaffold for the design of selective COX-2 inhibitors. One of the two phenyl groups bears at the 4-position either an aminosulfonyl (as in Celecoxib) or a methylsulfonyl (as in Rofecoxib and Valdecoxib), as the sulfonyl groups are known to be one of the determinants of COX-2 selectivity. The furazan analogues, deprived of the ability to release NO, were also considered for comparison purposes. Encouraged by the results achieved with this series of compounds, we decided to pursue the same concept of symbiotic drug with a different approach. While in the first case the COX-2 inhibitory pharmacophore and the NO-releasing moiety coincided, as the 1,2,5-oxadiazole N-oxide ring constituted the pentatomic core of the diarylheterocyclic structure, in our new project the two pharmacophores are distinct, with the NO-donor portion included as a substituent of the diarylheterocyclic scaffold. As a lead structure the imidazolic compound UR-8880, developed by Uriach group, was chosen, whose 4-methoxy group was replaced by nitrooxyalkyloxy chains of different length. All synthesised products were characterised from a structural point of view, the COX inhibition profile was studied in vitro and the binding mode was investigated through molecular modelling techniques.
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