An Analog Of Thiazole Which Has Potential Antithrombotic Activity With Low Toxicity

Chemical modification of a compound found active in preventing death in mice following intravenous administration of collagen led to the development of an inhibitor of collagen-induced platelet aggregation which was active at 1 ng/ml in human PRP, namely 4,5-bis(p-methoxyphenyl)-2- (trifluoromethyl)-thiazole (TFT). It did not inhibit ADP, thrombin or PGH₂-induced aggregation but inhibited the collagen-induced release of radioactivity from platelets labelled with radioactive serotonin. It was active in many animal species and in the rabbit it had a duration of activity of about 8 hours at 1 mg/kg (p.o.).

TFT has cyclooxygenase inhibitory activity, but unlike aspirin (A) or flurbiprofen (F), it showed no incidence of ulcers at 500 mg/kg p.o. in rats. However, again unlike A or F, it had very little anti-inflammatory activity as measured by the carrageenan-induced hind paw edema assay in rats. Its LD₅₀ in mice (i.p.) was greater than 1 gm/kg.

Thus TFT appears to be a potential antithrombotic agent with high antiplatelet specificity and a wide therapeutic margin as compared with A or F. The anti platelet action of TFT may be due to its inhibition of cyclooxygenase.