Studies on the synthesis and the antiplatelet activity of diarylpyrazole derivatives

Myocardial infarction (MI) may occur as a result of coronary atherothrombotic vascular disease is a leading cause of morbidity and mortality in many countries around the world. Platelets play a pivotal role in the pathogenesis of cardiovascular thrombosis. Following endothelial damage platelets adhere with the collagen in the subendothelium and aggregate upon their activation with different agonists and form a thrombus leading to a vascular blockage. Therefore, antiplatelet drugs are very important for prevention and treatment of recurrent acute coronary syndrome (ACS), MI and stroke. Current clinical antiplatelet therapies include aspirin, ADP P2Y12 receptor antagonists thienopyridine derivatives (i.e., clopidogrel), ?IIbß3 integrin (GPIIb/IIIa) antagonists (antibody abciximab, oligopeptid eptifibatide and nonpeptide tirofibane) and phosphodiesterase inhibitors dypyridamole and cilostazole.Many compounds owing to different chemical classes as antiplatelet agents have been developed. However, a limited number of SAR studies are available to explain the relationship between chemical structure and antiplatelet activity. Therefore, understanding the structural properties of developed compounds is very critical for coherent evaluation these studies and for developing better inhibitors. With this encouragement, we have synthesized a series of ester and amide derivatives starting from 5-(4-chlorophenyl)-1-(6-methoxypyridazin-3-yl)-1H-pyrazol-3-carboxylic acid (Compound 2). We tested the inhibitory activities of these compounds on AA-induced platelet aggregation at 100 µM screening dose and found that these compounds inhibited AA-induced platelet aggregation (96-100%). One of the compounds is also tested against collagen-induced platelet aggregation and found that the inhibitory activity was 67%.