These authors contributed equally to this work.
Diarylheterocycle Core Ring Features Effect in Selective COX-1 Inhibition
Article first published online: 25 JAN 2012
Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Volume 7, Issue 4, pages 629–641, April 2012
How to Cite
Perrone, M. G., Vitale, P., Malerba, P., Altomare, A., Rizzi, R., Lavecchia, A., Di Giovanni, C., Novellino, E. and Scilimati, A. (2012), Diarylheterocycle Core Ring Features Effect in Selective COX-1 Inhibition. ChemMedChem, 7: 629–641. doi: 10.1002/cmdc.201100530
- Issue published online: 27 MAR 2012
- Article first published online: 25 JAN 2012
- Manuscript Revised: 7 DEC 2011
- Manuscript Received: 17 NOV 2011
- MiUR. Grant Number: 20097FJHPZ_001
- molecular modeling;
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 (IC50=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.