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Pharmacological activities of a novel thienodiazepine derivative as a platelet-activating factor antagonist.
Arzneimittelforschung. 1990 Nov; 40(11):1201-5.A

Abstract

(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)

Authors+Show Affiliations

Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

2085331

Citation

Tsunoda, H, et al. "Pharmacological Activities of a Novel Thienodiazepine Derivative as a Platelet-activating Factor Antagonist." Arzneimittel-Forschung, vol. 40, no. 11, 1990, pp. 1201-5.
Tsunoda H, Sakuma Y, Harada K, et al. Pharmacological activities of a novel thienodiazepine derivative as a platelet-activating factor antagonist. Arzneimittelforschung. 1990;40(11):1201-5.
Tsunoda, H., Sakuma, Y., Harada, K., Muramoto, K., Katayama, S., Horie, T., Shimomura, N., Clark, R., Miyazawa, S., & Okano, K. (1990). Pharmacological activities of a novel thienodiazepine derivative as a platelet-activating factor antagonist. Arzneimittel-Forschung, 40(11), 1201-5.
Tsunoda H, et al. Pharmacological Activities of a Novel Thienodiazepine Derivative as a Platelet-activating Factor Antagonist. Arzneimittelforschung. 1990;40(11):1201-5. PubMed PMID: 2085331.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacological activities of a novel thienodiazepine derivative as a platelet-activating factor antagonist. A1 - Tsunoda,H, AU - Sakuma,Y, AU - Harada,K, AU - Muramoto,K, AU - Katayama,S, AU - Horie,T, AU - Shimomura,N, AU - Clark,R, AU - Miyazawa,S, AU - Okano,K, PY - 1990/11/1/pubmed PY - 1990/11/1/medline PY - 1990/11/1/entrez SP - 1201 EP - 5 JF - Arzneimittel-Forschung JO - Arzneimittelforschung VL - 40 IS - 11 N2 - (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) SN - 0004-4172 UR - https://www.unboundmedicine.com/medline/citation/2085331/Pharmacological_activities_of_a_novel_thienodiazepine_derivative_as_a_platelet_activating_factor_antagonist_ L2 - https://medlineplus.gov/bloodthinners.html DB - PRIME DP - Unbound Medicine ER -