Antiplatelet effects of 2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine in relation to its disposition in rats, rabbits and dogs.
KC-764 (2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine, CAS 94457-09-7) was evaluated for the inhibition of platelet aggregation and prostanoid production in rats, rabbits and dogs, comparing with acetylsalicylic acid (ASA). Correlations between the inhibitory action and plasma concentration of KC-764 were examined in rabbits. KC-764 was 200 times more potent than ASA in inhibiting collagen-induced rabbit platelet aggregation and TXA2 production in vitro. KC-764 exhibited more selective inhibition of TXA2 production over PGI2 production than ASA. The ratio of IC50's of PGI2 production to TXA2 production of KC-764 was 175 in rats, 72 in rabbits and 65 in dogs, respectively. Such a selectivity was also confirmed ex vivo. The depression of plasma TXB2 levels was well correlated with the ex vivo antiaggregatory activity in rabbits at oral doses of KC-764 ranging from 0.02-1.5 mg/kg. The concentrations/in vitro inhibitory activity relationship was expressed by a sigmoid Imax model equation. The ex vivo antiplatelet activity and prostanoid production were reconstructed with Imax model equation using the simulated plasma drug concentrations and in vitro Imax model parameters in all animals. The relationship could be applied for the prediction of the inhibitory activity of KC-764 in humans. These results indicate that KC-764 is a potent, selective and reversible antiplatelet drug, being different from ASA.
Ohmuro
S
S
Central Research Laboratories, Kyorin Pharmaceutical Co., Ltd., Nogi, Tochigi, Japan.
Sasahara
T
T
Taga
F
F
Ohkubo
H
H
Uchida
H
H
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D011464:Epoprostenol / Q000096:biosynthesis; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009539:Nicotinic Acids / Q000493:pharmacokinetics / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013928:Thromboxane A2 / Q000494:pharmacology; D014018:Tissue Distribution
D001643:Bridged Bicyclo Compounds; D009539:Nicotinic Acids; D010975:Platelet Aggregation Inhibitors; D013928:Thromboxane A2; C074536:KC 764; D011464:Epoprostenol; D001241:Aspirin