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

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Drug Discovery

Background:

• Selective cyclooxygenase (COX)-1 inhibitors show potential as cardioprotective agents.
• COX-1 is implicated in inflammatory processes and cancer development.
• Existing selective COX-1 inhibitors like SC-560 and mofezolac serve as structural templates.

Purpose of the Study:

• To design and synthesize novel compounds mimicking selective COX-1 inhibitors SC-560 and mofezolac.
• To evaluate the synthesized compounds for their activity and selectivity against COX-1 and COX-2.
• To explore potential therapeutic applications, including cardioprotection and anti-inflammatory effects.

Main Methods:

• Chemical synthesis of novel compounds incorporating triazole or benzene rings as central cores.
• In vitro enzymatic assays to determine inhibitory activity (IC50) against COX-1 and COX-2.
• Cell-based whole-blood antiplatelet assays to confirm in vitro COX-1 activity.
• Molecular docking simulations to elucidate binding interactions within the COX-1 active site.
• Cytotoxicity assessment using the human kidney HK-2 cell line.

Main Results:

• Synthesized compounds demonstrated significant activity and selectivity for COX-1 over COX-2.
• Compound 10a exhibited potent COX-1 inhibition (IC50 = 3 nM) and high selectivity (850 nM for COX-2), comparable to SC-560.
• Compounds 10a, 10c, 10d, and 3b showed potent antiplatelet activity in the nanomolar range (9-252 nM).
• Docking studies provided insights into the binding interactions within the COX-1 pocket.
• Selected compounds showed low toxicity in the tested human kidney cell line.

Conclusions:

• The novel triazole and benzene derivatives are effective selective COX-1 inhibitors.
• These compounds hold promise as potential cardioprotective and anti-inflammatory agents.
• The simplified synthetic approach offers an advantage for developing new COX-1 targeted therapeutics.