Synthesis and diuretic activity of alkyl- and arylguanidine analogs of N,N'-dicyclohexyl-4-morpholinecarboxamidine in rats and dogs.
Random screening identified N,N'-dicyclohexyl-4-morpholinecarboxamidine (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, when they were less potent than standard diuretics but showed furosemide-like natriuresis at > or = 100 mumol/kg. However, acute 1 at 61 and 90 mumol/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.
Departments of Medicinal Chemistry, Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001.
S C
SC
Perricone
S J
SJ
Humphrey
L L
LL
Skaletzky
B E
BE
Graham
R A
RA
Zandt
G R
GR
Zins
D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004232:Diuretics / Q000138:chemical synthesis / Q000494:pharmacology*; D004285:Dogs; D004347:Drug Interactions; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008914:Minoxidil / Q000494:pharmacology; D009025:Morpholines / Q000138:chemical synthesis / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D004232:Diuretics; D009025:Morpholines; D015221:Potassium Channels; C090435:N,N'-dicyclohexyl-4-morpholinecarboxamidine; C082658:U 37883A; D008914:Minoxidil; D000218:Adamantane