Indacrinone activities

Although it might seem that adrninistration of enantiomericaHy pure substances would always be preferred, the diuretic indacrinone (3), is an example of a dmg for which one enantiomer mediates the harmful effects of the other enantiomer (4). (+)-Indacrinone, the diureticaHy active enantiomer or eutomer causes uric acid retention. Fortunately, the other enantiomer distomer) causes uric acid elimination. Thus, adrninistration of a mixture of the two enantiomers, although not necessarily racemic, may have therapeutic value. 

The separation of enantiomers is a very important topic to the pharmaceutical industry. It is well recognized that the biological activities and bioavailabilities of enantiomers often differ [1]. To further complicate matters, the pharmacokinetic profile of the racemate is often not just the sum of the profiles of the individual enantiomers. In many cases, one enantiomer has the desired pharmacological activity, whereas the other enantiomer may be responsible for undesirable side-effects. What often gets lost however is the fact that, in some cases, one enantiomer may be inert and, in many cases, both enantiomers may have therapeutic value, though not for the same disease state. It is also possible for one enantiomer to mediate the harmful effects of the other enantiomer. For instance, in the case of indacrinone, one enantiomer is a diuretic but causes uric acid retention, whereas the other enantiomer causes uric acid elimination. Thus, administration of a mixture of enantiomers, although not necessarily racemic, may have therapeutic value. 

As well as an effect on the activity, different stereoisomers will also exhibit differences in other physiochemical properties, such as absorption, metabolism and elimination. For example, (—)norgestrel is absorbed at twice the rate of (+)norgestrel through buccal and vaginal membranes. The plasma half life of S-indacrinone is 2-5 hours whilst the value for the R isomer is 10-12 hours. 

Chiral synthesis using cinchinidium derived optically active PT catalyst Synthesis of indacrinone, a diuretic drug candidate... 

The pharmacodynamic properties of the natriuretic/uricosuric agent indacrinone have been studied in subjects given varying ratios of the (-b) and (—) enantiomers [68]. With respect to stereoselectivity in pharmacodynamic properties, (—)-indacrinone is a more potent natriuretic agent than the (-b) enantiomer. On the other hand, both enantiomers are equipotent with respect to uricosuric activity. The complexities of the pharmacodynamics of indacrinone and the merits of using different ratios of the enantiomers of indacrinone (instead of 1 1 in the racemate) are discussed in Chap. 5 (Sec. 3.3). 

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