COX-1 INHIBITORS AS ANTI-PLATELET AGENTS IN COVID-19

Coronavirus Disease 19 (COVID-19) is primarily a lung disease which frequently leads to major cardiovascular complications and a poor prognosis due to excessive platelet activation, uncontrolled immune/inflammatory reactions ("cytokine storm"), endothelial dysfunction, and coagulopathy.1 Aspirin, due to its anti-inflammatory and anti-platelet aggregation properties, has been evaluated as a potential therapeutic agent for COVID-19. Low-doses Aspirin (typically 75–81 mg/day) irreversibly inhibits platelet cyclooxygenase-1 (COX-1) by Ser530 acetylation preventing conversion of arachidonic acid into PGG2/PGH2, the latter in turn transformed by thromboxane synthase in thromboxane A2, thus resulting in an antithrombotic effect. Unfortunately, its use is limited by gastrointestinal side effects and aspirin resistance.2 Therefore, novel COX-1 inhibitors are needed. Mofezolac (Figure) is the most potent and selective COX-1 inhibitor administrated to humans as an anti-arthritis drug (Disopain™). It belongs to the diarylisoxazoles chemical class and used as a “hit compound” for Structure Activity Relationship (SAR) studies to design novel leads with antithrombotic activity. Replacing one or both mofezolac methoxyl with chemical groups with either increasing steric hindrance and capable to establish different interactions inside the COX-1 active site allowed the identification of novel COX-1 inhibitors. Evaluation of their effects on the blood coagulation cascade is ongoing.