Enantiomers of indacrinone: a new approach to producing an isouricemic diuretic

Racemic indacrinone is a potent loop diuretic with transient uricosuric properties in certain nonhuman primates and in man. After chronic treatment, hyperuricemia develops presumably because of enhanced proximal tubular urate reabsorption secondary to extracellular fluid volume contraction. The natriuretic and uricosuric activities are associated with both enantiomers, but the (-)-enantiomer is significantly more potent as a natriuretic agent than the (+). Acutely, in Cebus monkeys, both enantiomers appear to have similar uricosuric activity. The difference in the natriuretic potency between the two enantiomers provides the possibility of altering the enantiomer ratio from its naturally occurring 1:1 ratio to another combination which would enhance the uricosuric action [more (+) relative to (-)] while preserving the potent natriuretic action of the (-). In healthy volunteers, a 1:4 ratio [(-):(+)] was isouricemic after 7 days of treatment and a 1:8 mixture lowered mean serum urate by 13%. Presumably, the desired ratio of (-):(+) will be in the range 1:4-1:9. Further enhancement of the diuretic profile of this compound may be obtained by adding sufficient amiloride to produce isokalemia.