Antiplatelet activity and structure-activity relationship study of Pyrazolopyridine Derivatives as potential series for treating thrombotic diseases.
OBJECTIVE
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 SPARTAN' 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 - IC(50)=61 microM and 68 microM respectively) almost 5-fold more potent than aspirin (IC(50)=300 microM). These derivatives showed low theoretical toxicity risks in in silico ADMET screening and fulfilled the Lipinski rule of five, suggesting good oral biodisponibility.


CONCLUSIONS
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.
Laboratório de Antibióticos, Bioquímica e Modelagem Molecular (LABioMol)-Instituto de Biologia, Universidade Federal Fluminense, Niterói, RJ, Brazil.
R B
RB
Geraldo
M L
ML
Bello
L R S
LR
Dias
M A F
MA
Vera
T
T
Nagashima
P A
PA
Abreu
M B
MB
Santos
M G
MG
Albuquerque
L M
LM
Cabral
A C C
AC
Freitas
M V
MV
Kalil
C R
CR
Rodrigues
H C
HC
Castro
D001792:Blood Platelets / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013927:Thrombosis / Q000188:drug therapy* / Q000473:pathology
D010975:Platelet Aggregation Inhibitors; D011720:Pyrazoles; D011725:Pyridines; C118531:pyrazolopyridine