Effects of the new antiplatelet agent 2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine on platelet aggregation and thrombosis in experimental animals.
Antiplatelet and antithrombotic effects of KC-764 (2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine, CAS 94457-09-7) were studied. KC-764 inhibited arachidonic acid (AA)- and collagen-induced platelet aggregation with IC50s of 1.0 x 10(-8)-2.8 x 10(-7) mol/l for humans, rabbits, guinea pigs and dogs, and IC50s of 3.9 x 10(-6)-3.7 x 10(-5) mol/l for mice and rats in vitro. KC-764 inhibited AA- and collagen-induced aggregation with ID50s of 0.04-0.09 mg/kg p.o. in rabbits and dogs, and ID50 of 13.0 mg/kg p.o. in rats. These antiaggregatory activities of KC-764 were stronger than those of acetyl-salicylic acid (ASA), indometacin, cilostazol and ticlopidine. KC-764 inhibited the production of thromboxane B2 (TXB2) in rabbit platelet microsomes, washed platelets and reconstituted platelet rich plasma (RPRP) with IC50s of 2.9 x 10(-6) mol/l, 2.8 x 10(-7) mol/l and 4.3 x 10(-8) mol/l, respectively. The in vitro inhibitory activity of KC-764 on AA-induced platelet aggregation was more potent when RPRP was used rather than washed platelet suspension containing 30% rabbit plasma. ASA did not show such an augmentation. KC-764 prevented collagen- and AA-induced thrombosis at more than 1 mg/kg p.o. and more than 0.1 mg/kg i.v. in mice and rabbits. KC-764 showed the wider margin of dose between antiplatelet action and prolongation of bleeding time in rabbits than ASA and indometacin. These results indicated that KC-764 was a potent antithrombotic drug to prevent TXB2 production and less possible to induce untoward actions as compared with ASA or indometacin.
Momo
K
K
Technical Center of Development, Kyorin Pharmaceutical Co., Ltd., Tokyo, Japan.
Someya
K
K
Tachiiri
T
T
Mitsuoka
Y
Y
Nakamura
K
K
Imai
S
S
Ino
T
T
Ohkubo
H
H
D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors / Q000633:toxicity; D000818:Animals; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity; D001241:Aspirin / Q000494:pharmacology / Q000633:toxicity; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004285:Dogs; D004569:Electroencephalography; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009539:Nicotinic Acids / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D012119:Respiration / Q000187:drug effects; D013276:Stomach Ulcer / Q000139:chemically induced
D001643:Bridged Bicyclo Compounds; D016861:Cyclooxygenase Inhibitors; D005343:Fibrinolytic Agents; D009539:Nicotinic Acids; D010975:Platelet Aggregation Inhibitors; D016718:Arachidonic Acid; D000244:Adenosine Diphosphate; C074536:KC 764; D001241:Aspirin; D007213:Indomethacin