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

Abstract

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 '-substitutedphenylmethylene-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 M and 68 M respectively) almost 5-fold more potent than aspirin (IC50 300 M). These derivatives showed low theoretical toxicity risks in in silico ADMET screening and fulfilled the Lipinski rule of five, suggesting good oral biodisponibility. 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. J Atheroscler Thromb, 2010; 17:730-739.

Antiplatelet pyrazolopyridines derivatives: pharmacological, biochemical and toxicological characterization

“…According to our data, 3a (IC 50 ¼ 29.6 mM ± 2.7) is the most potent derivative of the N 0 -substituted-phenylmethylene-3-methyl-1,6-diphenyl-1H-pyrazolo [3,4-b]pyridine-4-carbohydrazide series with improved potency in comparison to ASA (IC 50 ¼ 40.5 mM ± 4.9) and ozagrel (IC 50 ¼ 53.12 mM ± 2.4). Interestingly, both derivatives 3a and ASA presented higher activity against human platelets (IC 50 ¼ 29.6 mM ± 2.7 and 40.5 mM ± 4.9, respectively) than their rabbit counterpart (3a -IC 50 ¼ 61 mM and ASA -IC 50 ¼ 300 mM) 8 . Since the IC 50 is related to the pharmacological potency of a drug 38 , this suggests a better pharmacological profile for 3a in comparison to ASA and ozagrel in both tested models.…”

“…Structure-activity relationship studies and molecular docking Molecular modeling calculations were performed as described elsewhere 8,[21][22][23][24] . Briefly, the three-dimensional structure of each derivative was built using SPARTAN (Wavefunction Õ , Irvine, CA) and the geometry optimization was obtained through the RM1 semi-empirical method followed by an ab initio calculation in quantum level using the 6-31G** basis set to obtain all stereoelectronic properties.…”

“…The Chemical Abstracts Service (CAS) register numbers of these compounds, previously described 8,14 , are 917369-16-5 (3a), 1340493-99-3 (3b), 1340493-48-2 (3d), 917369-21-2 (3h) and 1340494-21-4 (3j). Therefore, we evaluated their inhibition profile on human platelet aggregation against six different inducers (ARA, Collagen, ADP and Epinephrine, thrombin and the thromboxane receptor agonist U-44619).…”

“…They present a significant therapeutic potential including antimicrobial 9 , antichagasic 10 , analgesic 11 , anti-tumor 12 and antithrombotic activities 13 . Previously, N 0 -substituted-phenylmethylene-3-methyl-1,6-diphenyl-1H-pyrazolo [3,4-b]pyridine-4-carbohydrazide derivatives with antihemostatic profile have been synthesized and their chemical structures were characterized by our group (Table 2) 8,14 . The hit molecules previously found were shown to successfully inhibit platelet aggregation in rabbit platelet-rich plasma (PRP) using ARA as a proaggregant stimuli, highlighting compound 3a, whose potency (IC 50 ¼61 mM) was nearly five times better than ASA versus (IC 50 ¼300 mM).…”

“…This context prompts to the rational design and development of new antiplatelet drugs with lower adverse effects and/or better profile to treat these cardiovascular disorders 7 . Several families of chemical substances have arisen as potential antiplatelet drug prototypes, including pyrazolopyridines 8 . They present a significant therapeutic potential including antimicrobial 9 , antichagasic 10 , analgesic 11 , anti-tumor 12 and antithrombotic activities 13 .…”