The anti-platelet actions of FR122047, a novel cyclooxygenase inhibitor.
The anti-platelet actions of 1-[(4,5-bis(4-methoxyphenyl)-2- thiazoyl)carbonyl]-4-methylpiperazine hydrochloride (FR122047) were investigated in vitro and in vivo. FR122047 was 100 times more potent than aspirin against arachidonic acid- and collagen-induced human and guinea-pig platelet aggregation in vitro. Its actions on platelets were a result of cyclooxygenase inhibition. The single oral dose of FR122047 inhibited arachidonic acid- and collagen-induced aggregation with an ED50 of 280 micrograms/kg and 530 micrograms/kg, respectively, in guinea-pigs. The anti-platelet action was augmented 5-10 times by repeated administration for 4 days. At 1 mg/kg the inhibitory actions were prolonged for 48 h and the drug concentration was < 0.1 ng/ml in platelet-poor plasma at 24 h and 0.282 ng/ml in platelet-rich plasma at 48 h. The safety margin in rats (minimum ulcerogenic dose/ED50 for anti-platelet aggregation) of FR122047 was more than 70, while that of aspirin was only 1.2. These results indicate that FR122047 is concentrated in platelets and may be a useful anti-platelet agent.
Dohi
M
M
New Drug Research Laboratories, Fujisawa Pharmaceutical Company, Ltd., Osaka, Japan.
Sakata
Y
Y
Seki
J
J
Namikawa
Y
Y
Fujisaki
J
J
Tanaka
A
A
Takasugi
H
H
Motoyama
Y
Y
Yoshida
K
K
D000818:Animals; D001241:Aspirin / Q000494:pharmacology / Q000633:toxicity; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007509:Irritants / Q000633:toxicity; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D010879:Piperazines / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011453:Prostaglandins / Q000096:biosynthesis; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012669:Seminal Vesicles / Q000187:drug effects / Q000201:enzymology; D012756:Sheep; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology; D013844:Thiazoles / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D007509:Irritants; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D011453:Prostaglandins; D013844:Thiazoles; C085131:1-((4,5-bis(4-methoxyphenyl)-2-thiazoyl)carbonyl)-4-methylpiperazine; D008315:Malondialdehyde; D001241:Aspirin