Isoxazole and pyrazole core in COX-1 inhibitors

COX-1 isoenzyme has been recently reconsidered as therapeutic target, due to its crucial role exerted in a variety of pathological conditions, such as atherosclerosis, endothelial dysfunction, neuroinflammation, pain processing, pre-term labor and some type of cancers. Hence, highly selective COX-1 inhibitors might be particularly relevant for the treatment of several diseases [1]. 3-(5-Chlorofuran-2-yl)-5-methyl-4- phenylisoxazole, P6, a highly selective COX-1 inhibitor, recently uncovered by us[2], has been chosen as !lead compound" for structure-activity relationship studies [3].They assessed that the presence of the P6-furanyl group is crucial for COX-1 inhibitory potency and selectivity, as it is important the substituent size (bromine, chlorine or methyl group) on that furanyl. In addition, the replacement of a methyl by CF3-group at isoxazole C5 and the introduction of a substituent on the phenyl bonded to the isoxazole C4 still provide selective COX-1 inhibitors. Among the diarylheterocycle class of COX-1 inhibitors, the most studied COX-1 inhibitor is the SC-560 that has a pyrazole as a core ring instead of an isoxazole [4]. Thus, to identify the P6 and SC-560 common (if any) structural and/or electronic determinants responsible of the selective COX-1 inhibition, a series of new pyrazole analogues of P6 have been prepared by substituting the P6-isoxazole core ring with a pyrazole. The results of this investigation will be presented