Abstract
AY-31,906, exo-2-amino-4-[(bicyclo[2.2.1]hept-2-yl)amino-N-[[1- methylethyl)amino]carbonyl]-5-pyrimidinesulfonamide, exhibited potent diuretic and natriuretic activity in rats and dogs. After p.o. administration, AY-31,906 was 1.5- and 12.3-times more potent as a natriuretic than furosemide in rats and dogs, respectively, whereas it was 0.5- and 6.1-times as potent after i.v. administration. The maximum natriuretic effect of AY-31,906 in both species was similar to that observed with furosemide. At equiactive natriuretic p.o. doses in both species, AY-31,906 produced a greater increase in the urinary ratio of Na/K than furosemide, indicating a relative potassium-sparing effect. AY-31,906 produced significant increases in the fractional excretion of sodium and chloride in dogs at a dose that produced no statistically significant changes in the fractional excretion of potassium, glomerular filtration rate or renal plasma flow. After p.o. administration, the onset of activity of AY-31,906 occurred within the 1st hr in both rats and dogs and preliminary data demonstrated that the activity lasted for approximately 2 hr in rats and 4 hr in dogs. Clearance studies in conscious dogs suggest that AY-31,906 inhibited electrolyte reabsorption in the ascending limb of the loop of Henle and, unlike furosemide, AY-31,906 had no activity at the proximal tubule. These results indicate that AY-31,906 is a potent, high ceiling diuretic with relative potassium-sparing properties. The compound is well absorbed after p.o. administration with diuretic activity occurring in the 1st hr.
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|