The COX-1 isoenzyme plays a significant role in a variety of diseases, as it catalyzes the bioprocesses behind many health problems. Among the diarylheterocycle class of COX inhibitors, the isoxazole ring has been widely used as a central heterocycle for the preparation of potent and selective COX-1 inhibitors such as P6 [3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole]. The role of the isoxazole nucleus in COX-1 inhibitor selectivity has been clarified by preparing a set of new diarylheterocycles with various heterocycle cores. Replacement of isoxazole with isothiazole or pyrazole gave a drastic decrease in COX-1 inhibitory activity, whereas the introduction of an electron-donating group (EDG) on the N-aryl pyrazole allowed recovery of COX-1 inhibitory activity and selectivity. The EDG-equipped 5-(furan-2-yl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (17) selectively inhibits COX-1 activity (IC(50) =3.4 μM; 28% COX-2 inhibition at 50 μM), in contrast to its inactive analogue, 3-(furan-2-yl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole, which does not bear the methoxy EDG. Molecular docking studies of compound 17 into the binding site of COX-1 shed light on its binding mode.

Diarylheterocycle Core Ring Features Effect in Selective COX-1 Inhibition / Perrone, M. G.; Vitale, . P.; Malerba, P.; Altomare, A.; Rizzi, R.; Lavecchia, Antonio; DI GIOVANNI, Carmen; Novellino, Ettore; Scilimati, A.. - In: CHEMMEDCHEM. - ISSN 1860-7179. - 7:4(2012), pp. 629-641. [10.1002/cmdc.201100530]

Diarylheterocycle Core Ring Features Effect in Selective COX-1 Inhibition

LAVECCHIA, ANTONIO;DI GIOVANNI, CARMEN;NOVELLINO, ETTORE;
2012

Abstract

The COX-1 isoenzyme plays a significant role in a variety of diseases, as it catalyzes the bioprocesses behind many health problems. Among the diarylheterocycle class of COX inhibitors, the isoxazole ring has been widely used as a central heterocycle for the preparation of potent and selective COX-1 inhibitors such as P6 [3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole]. The role of the isoxazole nucleus in COX-1 inhibitor selectivity has been clarified by preparing a set of new diarylheterocycles with various heterocycle cores. Replacement of isoxazole with isothiazole or pyrazole gave a drastic decrease in COX-1 inhibitory activity, whereas the introduction of an electron-donating group (EDG) on the N-aryl pyrazole allowed recovery of COX-1 inhibitory activity and selectivity. The EDG-equipped 5-(furan-2-yl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (17) selectively inhibits COX-1 activity (IC(50) =3.4 μM; 28% COX-2 inhibition at 50 μM), in contrast to its inactive analogue, 3-(furan-2-yl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole, which does not bear the methoxy EDG. Molecular docking studies of compound 17 into the binding site of COX-1 shed light on its binding mode.
2012
Diarylheterocycle Core Ring Features Effect in Selective COX-1 Inhibition / Perrone, M. G.; Vitale, . P.; Malerba, P.; Altomare, A.; Rizzi, R.; Lavecchia, Antonio; DI GIOVANNI, Carmen; Novellino, Ettore; Scilimati, A.. - In: CHEMMEDCHEM. - ISSN 1860-7179. - 7:4(2012), pp. 629-641. [10.1002/cmdc.201100530]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/423743
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