Cleavable Novel Thienopyridine Derivatives as Potent Antithrombotic Agents

Abstract

Thienopyridine derivatives are specifically designed for utilization in antithrombotic therapy to help combat cardiovascular disorders linked to thrombosis. This study introduces new thienopyridine derivatives with superior therapeutic efficacy through synergies by dual functional compounds, developed as antithrombotic agents. Through computational design, we discovered 32 compounds out of a library of 100 compounds that exhibit efficacy. The compounds are synthesized by multiple steps and subsequently purified using chromatographic procedures to achieve a purity level of >99%. Using the ADP-induced platelet aggregation assay, we have found 4 active test compounds (ACG-0173-19, ACG-0173-37, ACG-A-04, and ACG-B-03) out of a total of 32 compounds. On the other hand, ACG-0173-19, ACG-0173-37, ACG-A-04, and ACG-B-03 have demonstrated the highest percentage activity on factor Xa (FXa) inhibition. The ACG-A-04 chemical exhibited the highest hydrophilicity, specifically in terms of its aqueous solubility. It had a solubility of 0.44 mg/mL in pH 5.8, 0.29 mg/L in pH 6.2, and 0.145 mg/L in pH 7.4 buffers. In comparison, the standards APX-01 (apixaban) and PRG-01(prasugrel) had lower hydrophilicity. Based on cytotoxicity investigations, it was determined that the test substances do not exhibit harmful effects. The results indicated that the test chemicals can undergo hydrolysis in blood plasma rather than in other organs. Among the four test drugs, ACG-1073-19 exhibited an unbound fraction of 44.1%, which is twice as high as the standards (apixaban). ACG-1073-37 demonstrates superior plasma protein binding (33.2%) compared to all other test compounds. The compounds resulted in a higher expression of CD61, CD42b, and CD62P in platelets compared to the control. The ACG-1073-37 molecule had a Caco-2 permeability of 51%, which is extremely close to the Caco-2 permeability of the control medicines (55% for APX-01 and 62% for PRG-01). Through the assessment of microsomal stability, it was determined that ACG-1073-37 and ACG-A-04 exhibited metabolic stability for 42.4 and 34.14 min, respectively.