SC‐560 and mofezolac isosteres as new potent COX‐1 selective inhibitors with antiplatelet effect

Abstract

Selective cyclooxygenase (COX)-1 inhibitors can be employed as potential cardioprotective drugs. Moreover, COX-1 plays a key role in inflammatory processes and its activity is associated with some types of cancer. In this work, we designed and synthesized a set of compounds that structurally mimic the selective COX-1 inhibitors, SC-560 and mofezolac, the central cores of which were replaced either with triazole or benzene rings. The advantage of this approach is a relatively simple synthesis in comparison with the syntheses of parent compounds. The newly synthesized compounds exhibited remarkable activity and selectivity toward COX-1 in the enzymatic in vitro assay. The most potent compound, 10a (IC 50 = 3 nM for COX-1 and 850 nM for COX-2), was as active as SC-560 (IC 50 = 2.4 nM for COX-1 and 470 nM for COX-2) toward COX-1 and it was even more selective. The in vitro COX-1 enzymatic activity was further confirmed in the cell-based whole-blood antiplatelet assay, where three out of four selected compounds (10a,c,d, and 3b) exerted outstanding IC 50 values in the nanomolar range (9-252 nM). Moreover, docking simulations were performed to reveal key interactions within the COX-1 binding pocket. Furthermore, the toxicity of the selected compounds was tested using the normal human kidney HK-2 cell line.

COX inhibitory profiles of a series of thiadiazole-benzothiazole hybrids

“…Furthermore, it is understood that the long-term use of NSAIDs diminishes the incidence of some diseases including Alzheimer's Disease and some types of cancer. There is only one selective COX-1 inhibitor (mofezolac) (Figure 1) currently prescribed just in Japan for the treatment of pain and inflammation, and therefore the search for selective inhibitors of COX-1 has come into prominence [9][10][11].…”