Čeština
EnglishSC-560 and mofezolac isosteres as new potent COX-1 selective inhibitors with antiplatelet effect
Šíša M., Konečný L., Temml V., Carazo A., Mladěnka P., Landa P.
ARCHIV DER PHARMAZIE : e2200549, 2023
Keywords: cyclooxygenase, cytotoxicity, docking, platelets, selectivity
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 (IC50= 3 nM for COX‐1 and 850 nM for COX‐2), was as active as SC‐560 (IC50= 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, and3b) exerted outstanding IC50 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.
DOI: 10.1002/ardp.202200549
IEB authors: Přemysl Landa, Miroslav Šíša
ARCHIV DER PHARMAZIE : e2200549, 2023
Keywords: cyclooxygenase, cytotoxicity, docking, platelets, selectivity
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 (IC50= 3 nM for COX‐1 and 850 nM for COX‐2), was as active as SC‐560 (IC50= 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, and3b) exerted outstanding IC50 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.
DOI: 10.1002/ardp.202200549