DS-4574

We evaluated the protective effect of DS-4574 (6-(2-cyclohexylethyl)-[1,3,4]thiadiazolo[3,2-a]-1,2,3- triazolo[4,5-d]pyrimidin-9(3H)-one), a peptidoleukotriene receptor antagonist, against intestinal mucosal injury evoked by endotoxin in rats by exploring changes in hematocrit and plasma leakage along with morphological features. Treatment with Escherichia coli endotoxin (5 mg/kg i.v.) alone elicited hemoconcentration, vasocongestion and a marked mucosal necrosis. DS-4574 (10-50 mg/kg) effectively prevented these changes on either oral or intraduodenal administration. These results demonstrate that peptidoleukotrienes may be key mediators in the intestinal injury induced by endotoxin in rats.

An anti-allergic agent, 6-(2-cyclohexylethyl)-[1,3,4]thiadiazolo[3,2-a]-1,2,3-triazolo[4,5-d]-pyrimidin-9 (3H)-one (DS-4574), is a newly synthesized drug in our laboratoryA novel metabolic M-6, having a newly introduced hydroxyl group, was isolated and identified from human urine obtained from healthy Japanese volunteers who had received this drug orally.Since a new chiral center was created at C3-position on the cyclohexyl ring, this hydroxylation was expected to be product-stereoselective, theor. yielding 2 stereoisomeric alcs.HPLC anal. was carried out for determination of the (+)/(-) ratio of M-6 isolated from human urine.Chiralcel OD was used for separation of the enantiomers, and the <(+)/(-) ratio of M-6 was determined from the optical activity and UV absorption.As a result, (+)/(-) ratio of 1:21 was obtained, suggesting that hydroxylation of DS-4574 to M-6 in human is product-stereoselective.