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Pharmacology of a potent platelet-activating factor antagonist: Ro 24-4736.
J Pharmacol Exp Ther. 1991 Oct; 259(1):78-85.JP

Abstract

Ro 24-4736, (5-(3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]-2-propynyl)phenanthri din- 6(5H)-one), has been identified as a potent, selective, p.o.-active platelet-activating factor (PAF) antagonist with a long duration of action. In vitro, Ro 24-4736 competes with [3H]PAF for its receptor site on dog platelets with an IC50 of 9.8 +/- 1.0 nM and selectively inhibits PAF-induced aggregation of guinea pig, dog and human platelets with concentration dependence. Ro 24-4736 dose-dependently inhibits in vivo bronchoconstriction (ID50 of 0.006-mg/kg p.o.) and ex vivo platelet aggregation (ID50 of 0.004 mg/kg p.o.) induced by PAF in guinea pigs. Time course studies show complete blockade of PAF-induced platelet aggregation (ex vivo) up to 8 hr after a single p.o. dose of 0.03 mg/kg as well as a long duration of action in vivo (30 hr). The in vivo PAF antagonistic activity is specific because, even at high p.o. doses (up to 10 mg/kg), Ro 24-4736 shows no inhibitory activity toward the bronchoconstrictor effects of leukotriene D4 or histamine. In comparison with other PAF antagonists evaluated in this guinea pig model, Ro 24-4736 is markedly superior in terms of p.o. potency, bioavailability and p.o. duration of action. Studies were also performed with Ro 24-4736 in additional in vivo models. When administered p.o. to sensitized guinea pigs, the drug attenuates inhaled antigen-induced airway hyper-reactivity without effect on bronchoalveolar lavage leukocyte accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors+Show Affiliations

Department of Pharmacology, Hoffmann-La Roche, Inc., Nutley, New Jersey.No 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

1656030

Citation

Crowley, H J., et al. "Pharmacology of a Potent Platelet-activating Factor Antagonist: Ro 24-4736." The Journal of Pharmacology and Experimental Therapeutics, vol. 259, no. 1, 1991, pp. 78-85.
Crowley HJ, Yaremko B, Selig WM, et al. Pharmacology of a potent platelet-activating factor antagonist: Ro 24-4736. J Pharmacol Exp Ther. 1991;259(1):78-85.
Crowley, H. J., Yaremko, B., Selig, W. M., Janero, D. R., Burghardt, C., Welton, A. F., & O'Donnell, M. (1991). Pharmacology of a potent platelet-activating factor antagonist: Ro 24-4736. The Journal of Pharmacology and Experimental Therapeutics, 259(1), 78-85.
Crowley HJ, et al. Pharmacology of a Potent Platelet-activating Factor Antagonist: Ro 24-4736. J Pharmacol Exp Ther. 1991;259(1):78-85. PubMed PMID: 1656030.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacology of a potent platelet-activating factor antagonist: Ro 24-4736. AU - Crowley,H J, AU - Yaremko,B, AU - Selig,W M, AU - Janero,D R, AU - Burghardt,C, AU - Welton,A F, AU - O'Donnell,M, PY - 1991/10/1/pubmed PY - 1991/10/1/medline PY - 1991/10/1/entrez SP - 78 EP - 85 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 259 IS - 1 N2 - Ro 24-4736, (5-(3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]-2-propynyl)phenanthri din- 6(5H)-one), has been identified as a potent, selective, p.o.-active platelet-activating factor (PAF) antagonist with a long duration of action. In vitro, Ro 24-4736 competes with [3H]PAF for its receptor site on dog platelets with an IC50 of 9.8 +/- 1.0 nM and selectively inhibits PAF-induced aggregation of guinea pig, dog and human platelets with concentration dependence. Ro 24-4736 dose-dependently inhibits in vivo bronchoconstriction (ID50 of 0.006-mg/kg p.o.) and ex vivo platelet aggregation (ID50 of 0.004 mg/kg p.o.) induced by PAF in guinea pigs. Time course studies show complete blockade of PAF-induced platelet aggregation (ex vivo) up to 8 hr after a single p.o. dose of 0.03 mg/kg as well as a long duration of action in vivo (30 hr). The in vivo PAF antagonistic activity is specific because, even at high p.o. doses (up to 10 mg/kg), Ro 24-4736 shows no inhibitory activity toward the bronchoconstrictor effects of leukotriene D4 or histamine. In comparison with other PAF antagonists evaluated in this guinea pig model, Ro 24-4736 is markedly superior in terms of p.o. potency, bioavailability and p.o. duration of action. Studies were also performed with Ro 24-4736 in additional in vivo models. When administered p.o. to sensitized guinea pigs, the drug attenuates inhaled antigen-induced airway hyper-reactivity without effect on bronchoalveolar lavage leukocyte accumulation.(ABSTRACT TRUNCATED AT 250 WORDS) SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/1656030/Pharmacology_of_a_potent_platelet_activating_factor_antagonist:_Ro_24_4736_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=1656030 DB - PRIME DP - Unbound Medicine ER -