SYNTHESIS AND DIURETIC ACTIVITY OF ALKYLGUANIDINE AND ARYLGUANIDINE ANALOGS OF N,N'-DICYCLOHEXYL-4-MORPHOLINECARBOXAMIDINE IN RATS AND DOGS

Random screening identified N,N'-dicyclohexyl-4-morpholinecarboxamide (U-18177, 1) as an orally effective nonkaliuretic diuretic in rats. The diuretic profile of 1 and its 1-adamantyl analog (U-37883A, 4) was confirmed orally in dogs, where they were less potent than standard diuretics but showed furosemide-like natriuresis at greater than or equal to 100 mu mol/kg. However, acute 1 at 61 and 90 mu mol/kg iv resulted in lethal:cardiac toxicity in dogs. Many analogs of 1 exhibited qualitatively similar diuretic profiles, but none was sufficiently safe to warrant development. Compound 1 also reversed minoxidil's vasodilation in dogs, which led to vascular interaction studies suggesting that analog 4 may block ATP-sensitive K channels. This K channel-blocking mechanism may contribute to the diuretic activity of the series. This is the first report broadly characterizing the diuretic activity of 1 and representative guanidine analogs in rats and dogs and its toxicity and minoxidil-blocking effects in dogs.