Enantiomers pharmacological profile

The enantioselective reduction of unsaturated alcohol derivatives has been applied to the synthesis of several biologically active compounds (Scheme 24.12). Warfarin (123, R=H) is an important anticoagulant that is normally prescribed as the racemate, despite the enantiomers having dissimilar pharmacological profiles. One of the earliest reported uses of DuPhos was in the development of a chiral switch for this bioactive molecule, facilitating the preparation of (R)- and (S)-warfarin [184]. Although attempted reduction of the parent hydroxycoumarin 122 (R=H) led to formation of an unreactive cyclic hemiketal, hydrogenation of the sodium salt proceeded smoothly with Rh-Et-DuPhos in 86-89% ee. 

The dopamine D2 agonist SAR area has been reviewed by Hacksell and coworkers from the perspective of stereochemistry and pharmacological profiles of the enantiomers of the compounds synthesized by that research group during a period of 10 years. The structural classes surveyed were 3-phenylpiperidines, 2-aminotetralins and their ring-methylated analogues and octahydrobenzo[/]quinolines (OHB[f]Qs) [60]. 

Since cetirizine dihydrochloride (4) is a mixture of two enantiomers, they have been separated and tested individually. The levorotatory enantiomer of cetirizine displays a better pharmacological profile than the racemic mixture, and is currently... 

Wellbutrin and Zyban are marketed as a racemic mixture of bupropion as its hydrochloride salt. However, over the past 15 years there has been an increasing trend to develop new drugs as single enantiomers. Several publications have demonstrated that the enantiomers of many chiral compounds have distinct pharmacological profiles and the benefits in using a single enantiomer over the racemate... 

The USP [7] provides extensive discussion on impurities in sections 1086 (Impurities in Offical Articles), 466 (Ordinary Impurities), and 467 (Organic Volative Impurities). A total impurity level of 2.0% has been adopted as a general limit for bulk pharmaceuticals [5]. There have been no levels established for the presence of enantiomers in a drug substance/ product. This is primarily because the enantiomers may have similiar pharmacological and toxicological profiles, enantiomers may rapidly interconvert in vitro and/or in vivo, one enantiomer is shown to be pharmacologically inactive, synthesis or isloation of the perferred enantiomer is not practical, and individual enantiomers exhibit different pharmacologic profiles and the racemate produces a superior therapeutic effect relative to either enantiomer alone [8,9]. 

In vivo, racemic dobutamine increases the inotropic activity of the heart to a much greater extent than it increa.ses chronotropic activity. This pharmacological profile has led to its use in treating congestive heart failure. Since /3 receptors are involved positively in both inotropic and chronotropic effects of the heart, the selective inotropic effect. seen with dobutamine cannot simply be due to its activity at P% receptors. Rather, this effect is the result of a combination of the inotropic effect of (-t- )-dohutamine on Px receptors and that of (-)-dobutamine mediated through 0 receptors. Thus, this is a case where a racemic mixture provides a more desirable pharmacological and therapeutic cITect than would cither enantiomer alone. 

TABLE 26.4 Differences in pharmacological profile of couples of enantiomers ... 

It is worth noting that the compounds mentioned above have a stereogenic centre at C-3 and their resolution may be crucial in view of the potentially different pharmacological profile of the pure enantiomers. Since the reaction between the amine and isocyanate is unlikely to cause racemization at C-3, it would be possible to obtain the enantiomerically pure ureas after separation of the corresponding amines, thus highlighting the strategic importance of such a key intermediate. 

A Differences in potency and antagonism between two enantiomers B Differences in the pharmacological profile of two enantiomers... 

Besides the difference in potency, it often happens that two enantiomers show differences in their pharmacological profile. In such a case, resolving the racemic mixture can generate two pharmacologically different and useful compounds and also separate the more active compound... 

Whenever possible, pure enantiomers are nowadays developed and introduced into the pharmaceutical market the only exception are eompounds, where identical pharmacological profiles are found for both enantiomers or compounds, where the much higher price of one enantiomer, as compared to the racemate, precludes such a selection. 

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