Effect of SC 38249, a Novel Substituted Imidazole, on Platelet Aggregation In Vitro and In Vivo

N Lad; A C Honey; D O Lunt; R F G Booth; J Westwick; P W Manley; D P Tuffin

doi:10.1055/s-0038-1642747

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1988; 59(02): 164-170
DOI: 10.1055/s-0038-1642747

Original Articles

Schattauer GmbH Stuttgart

Effect of SC 38249, a Novel Substituted Imidazole, on Platelet Aggregation In Vitro and In Vivo

N Lad

Searle Research & Development, High Wycombe, Buckinghamshire, UK

,

A C Honey

Searle Research & Development, High Wycombe, Buckinghamshire, UK

,

D O Lunt

Searle Research & Development, High Wycombe, Buckinghamshire, UK

,

R F G Booth

Searle Research & Development, High Wycombe, Buckinghamshire, UK

,

J Westwick

¹Department of Pharmacology, Royal College of Surgeons of England, Lincoln's Inn Fields, London WC2A 3PN, UK

,

P W Manley

Searle Research & Development, High Wycombe, Buckinghamshire, UK

,

D P Tuffin

Searle Research & Development, High Wycombe, Buckinghamshire, UK

› Author Affiliations

Abstract

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Summary

SC 38249 ((RS)-l-(2,3-bis-[(4-methoxyphenyl)methoxy] propyl)-lH-imidazole) caused dose-related inhibition of collagen- induced thromboxane A₂ formation in human platelet rich plasma (IC₅₀: 9.9 ± 1.0 μM) accompanied by a dose-dependent increase in plasma PGE₂. Broad inhibitory activity was evident against human platelet aggregatory and secretory responses in vitro.IC₅₀ values of 11.9 ± 1.9 μM (0.64 mM arachidonic acid), 18.3 ± 3.8 μM (0.5 μg ml−^-1collagen) and 37.6 ± 6.1 μM (25 nM Paf-acether) were obtained against maximum increase in PRP light transmission achieved by each agonist. Although less potent, SC 38249 retained significant inhibitory activity against PRP responses induced by a higher (3.0 μg ml−^-1) concentration of collagen (IC₅₀: 272.5 ± 24.6 μM), and against Paf-acether-induced responses in PRP pre-treated with 10 μM indomethacin (I.C.₅₀: 192.0 ± 16.1 μM).Experimental animal studies confirmed the in vitroanti-aggregatory efficacy of SC 38249, since significant inhibitory activity was observed against Paf-acether and ADP-induced responses in dog PRP ex vivo,anti-Forssman antibody-induced thrombocytopoenia in anaesthetized guinea pigs, and collagen-induced intravascular aggregation in anaesthetized rabbits. Thus, SC 38249 is a novel thromboxane synthase inhibitor which possesses interesting anti-aggregatory properties which cannot wholly be attributed to prevention of platelet thromboxane A₂ formation.

Keywords

SC 38249 - Thromboxane synthase inhibitor - Anti-aggregatory properties

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References

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