Pharmacological activities of a novel thienodiazepine derivative as a platelet-activating factor antagonist.
(S)-(+)-6-(2-Chlorophenyl)-3-cyclopropanecarbonyl-8,11- dimethyl - 2,3,4,5 - tetrahydro - 8H - pyrido[4',3':4,5] thieno[3,2-fl-[1,2,4]triazolo]4,3-a][1,4]diazepine (E-6123) is a newly synthesized platelet-activating factor (PAF) antagonist. The effects of E-6123 on in vitro and in vivo PAF-induced responses were investigated. The IC50 values of E-6123 on 3H-PAF binding to human and guinea pig platelets were 2.7 and 3.0 nmol/l, respectively, and those on PAF-induced platelet aggregation in platelet-rich plasma of human, guinea pig and beagle dog were 10.1, 14.7 and 16 nmol/l, respectively. Oral administration of E-6123 at 3 and 10 micrograms/kg to dogs inhibited ex vivo PAF-induced platelet aggregation in a dose-dependent manner. In guinea pigs, E-6123 at 3 micrograms/kg completely inhibited ex vivo PAF-induced platelet aggregation up to 8 h and the inhibition was still significant at 24 h after administration. Occupancy of the platelet PAF receptor by E-6123 at 3 h and 24 h after administration amounted to 80% and 56%, respectively. Bronchoconstriction induced by PAF injection in guinea pigs was inhibited dose-dependently by oral or intravenous administration of E-6123 at similar doses. The IC50 value of E-6123 at 3 h after oral administration was 1 microgram/kg. Oral administration of E-6123 at 3 micrograms/kg inhibited the bronchoconstriction by more than 90% up to 8 h. Hemato-concentration induced by PAF injection in guinea pigs was inhibited by oral administration of E-6123 at 10 micrograms/kg. E-6123 also protected mice from PAF injection-induced death in a dose-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)
Tsunoda
H
H
Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
Sakuma
Y
Y
Harada
K
K
Muramoto
K
K
Katayama
S
S
Horie
T
T
Shimomura
N
N
Clark
R
R
Miyazawa
S
S
Okano
K
K
D000284:Administration, Oral; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D016084:Bronchoconstriction / Q000187:drug effects; D004285:Dogs; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D051379:Mice; D008813:Mice, Inbred ICR; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D013045:Species Specificity; D014230:Triazoles / Q000494:pharmacology*
D001381:Azepines; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D014230:Triazoles; C068033:E 6123