Antiplatelet activity and structure-activity relationship study of Pyrazolopyridine Derivatives as potential series for treating thrombotic diseases

作者：Geraldo R B; Bello M L; Dias L R S; Vera M A F; Nagashima T; Abreu P A; Santos M B; Albuquerque M G; Cabral L M; Freitas A C C; Kalil M V; Rodrigues C R; Castro H C^*

来源：Journal of Atherosclerosis and Thrombosis, 2010, 17(7): 730-739.

DOI：10.5551/jat.3293

• Antiplatelets
• Stroke
• Structure-activity relationship (SAR)

Aim: Platelets plays a central role in hemostatic processes and consequently are similarly involved in pathological processes, such as arterial thrombosis and atherosclerosis. Herein we described the synthesis, antiplatelet profile and structure-activity relationship (SAR) of a new series of N'-substituted-phenylmethylene-1H-pyrazolo[3,4-b] pyridine-carbohydrazide derivatives (3a-3k).
Methods: These compounds were synthesized in good yield and tested in platelet aggregation assays using collagen, ADP and arachidonic acid as agonists. We also performed a SAR studies using SPAR-TAN' 08 program, in silico ADMET screening and the Lipinski "rule of five" using Osiris Property Explorer and molinspiration on-line programs.
Results: Interestingly, the new compounds were active against collagen and arachidonic acid (AA) with the two most actives compounds (3a and 3c - IC50 = 61 mu M and 68 mu M respectively) almost 5-fold more potent than aspirin (IC50 = 300 mu M). These derivatives showed low theoretical toxicity risks in in silico ADMET screening and fulfilled the Lipinski rule of five, suggesting good oral bio-disponibility.
Conclusion: This work showed carbohydrazide group as potential for designing new antiplatelets. On that purpose, 3a and 3c may act as prototypes to generate more efficient and safe molecules for treating thrombotic diseases.

• 出版日期2010