THE IN VIVO PRODUCTION OF A POTENT, LONG-ACTING HYPOTENSIVE METABOLITE FROM DIALLYLMELAMINE

¹ Pharmacology Research Laboratories, The Upjohn Company, Kalamazoo, Michigan

Diallylmelamine [2,4-diamino-6-(diallyla-mino)-s-triazine] (DAM) was slowly but completely absorbed from the gastrointestinal tract of rats and dogs. Distribution studies in rats revealed a high concentration of unchanged drug in gastric lining and contents but gave no clue regarding its hypotensive activity. The compound was extensively metabolized by all species studied and metabolites were largely excreted in the urine within 24 hours. The time course of the hypotensive action of DAM coincided with blood levels of metabolites rather than of parent compound. SKF 525A inhibited the metabolism of DAM in rats and caused increased accumulation of certain chloroformsoluble metabolites in the blood. These changes were accompanied by a prolongation of the hypotensive response. Three metabolites were isolated from the urine of rats treated with DAM and were tested for hypotensive activity. One of these (metabolite B) lowered blood pressure. The onset of action was rapid and the potency was substantially greater than that of DAM. Metabolite B, a ring N-oxide of the parent molecule, is believed to account for the hypotensive activity of DAM.