Enantiomers of Indacrinone: A New Approach to Producing an Isouricemic Diuretic

Abstract

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.

Effect on Serum Uric Acid Levels of Drugs Prescribed for Indications other than Treating Hyperuricaemia

“…The (-) is natriuretic and the (+) is uricosuric [82][83][84]. However, ototoxicity and other side effects limit the use of these diuretics [82][83][84][85].…”

“…Ethacrynic acid causes minor urate retention and indacrinone, a loop diuretic, has two enantiomers with different pharmacologic activity [82][83][84]. The (-) is natriuretic and the (+) is uricosuric [82][83][84].…”

Enantiomeric drug development: Issues, considerations, and regulatory requirements

“…A good example is that of indacrinone. 33,34 The dextroenantiomer of indacrinone exhibits a strong diuretic action and also causes a retention of uric acid. However, the levo-enantiomer, completely negates the side effects of the eutomer because of its uricosuric properties.…”

Uricosuric and Diuretic Activities of DR-3438 in Dogs and Rabbits

“…Indacrinone has been reported to possess both natriuretic and uricosuric properties in animals (24) and humans (25). The uricosuric activity of in dacrinone is too transient and is not sufficient at clinically used doses to prevent the rise in urate that is normally observed after diuretic therapy (26)(27)(28).…”