Enantiomers pharmacological properties

The Cahn-Ingold-Prelog (CIP) rules stand as the official way to specify chirahty of molecular structures [35, 36] (see also Section 2.8), but can we measure the chirality of a chiral molecule. Can one say that one structure is more chiral than another. These questions are associated in a chemist s mind with some of the experimentally observed properties of chiral compounds. For example, the racemic mixture of one pail of specific enantiomers may be more clearly separated in a given chiral chromatographic system than the racemic mixture of another compound. Or, the difference in pharmacological properties for a particular pair of enantiomers may be greater than for another pair. Or, one chiral compound may rotate the plane of polarized light more than another. Several theoretical quantitative measures of chirality have been developed and have been reviewed elsewhere [37-40]. 

Although most physical properties of enantiomers are identical, pharmacological properties may be different. There are examples of compounds where ... 

Sotalol, as the racemate (a 1 1 mixture of the d- and 1-enantiomers), has a well-documented class Ill-antiarrhythmic activity, without showing the various side-effects of amiodarone. The -adrenoceptor blockade by this agent, however, limits its use in patients with heart failure. Dofetilide is an example of a newer, rather pure class in-antiarrhythmic, virtually devoid of other pharmacological properties. 

Chirality plays a major role in biological processes and enantiomers of a particular molecule can often have different physiological properties. In some cases, enantiomers may have similar pharmacological properties with different potencies for example, one enantiomer may play a positive pharmacological role, while the other can be toxic. For this reason, advancements in asymmetric synthesis, especially in the pharmaceutical industry and life sciences, has led to the need to assess the enantiomeric purity of drugs. Chromatographic chiral separation plays an important role in this domain. Today, there are a large number of chiral stationary phases on the market that facilitate the assessment of enantiomeric purity. 

Frequently one of the enantiomers does not have active pharmacologic properties. In such a case, the drug formulation should not include a chemical moiety that does not have therapeutic value once the separation technique is available and is considered to be economical. In addition to physiological activities, stereospecificity influences the physicochemical properties of drugs. Let s take as an example the enantiomer of ibuprofen compared with the race-mate. The chiral compound has higher aqueous solubility, higher density, and better flowability, but a lower intrinsic dissolution rate. ... 

Both enantiomers of E-3710 (318), a novel analgesic, were prepared and their absolute stereochemistries assigned their pharmacological properties were compared with those of the racemic and no significant difference was observed <93BMC269). 

GC is basically a technique for analytical enantioseparations. However, micropreparative separations are also feasible using this technique. The most impressive example of the application of chiral GC for micropreparative enantioseparation of drug enantiomers is the chiral inhalation anesthetic drug, enflurane. According to recent data, the enantiomers of isoflurane may have different pharmacological properties [94]. For the isomeric compound enflurane (Fig. 3) a more intensive metabolism was established for the (ft)-(-)-enantiomer compared with the (S)-(+)-enantiomer [95]. Enflurane is a gas and therefore, the most favorable method for the enantioseparation will certainly be GC. Analytical-scale enantioseparations of this compound have been reported using various CD derivatives as CSPs [97]. The micro-... 

The kinetics of excretion are a direct consequence of the kinetics of metabolic transformations. The faster a drug is metabolized, the faster its elimination can be expected. In accordance with this assertion, rats given R,S( ), S(+), and R(-)-amphetamine, were found to excrete less (+)-p-hydroxy-amphetamine than its (-)-isomer this may be the basic explanation of the more pronounced pharmacological properties of the dextro-, compared to the levoampheta-mine. For the hypnotic agent hexobarbital, the ehmination half-life in man is about three limes longer for the more active (-l-)-isomer then for the less active ( )-isomer. This was attributed to a difference in hepatic metabolic clearance and not in volumes of distribulion or plasma binding between the enantiomers. " ... 

Tranylcypromine is a chiral monoamine oxidase inhibitor used in the treatment of depression. The drug is similar to mefloquine in that it is contains a diastereomeric structure but is only administered as the 50 50 combination of the (- -)-lS,2R and (—)-lR,2S species. The enantiomers possess differences in their pharmacological properties in that (-I-) tranylcypromine is much more effective than its antipode in MAO inhibition, but the (—) enantiomer causes greater diminution of catecholamine reuptake and release than (-I-) enantiomer [147]. With respect to its pharmacokinetics (Table 1), the (-I-) enantiomer seemed to be cleared via the oral route 4 to 8 times more rapidly than antipode based on significantly... 

It is generally sufficient to carry out toxicity studies on the racemate. If toxicity other than that predicted from the pharmacological properties of the drug occurs at relatively low multiples of the exposure planned for clinical trials, the toxicity study should be repeated with the individual isomers to ascertain whether only one enantiomer was responsible for the toxicity. If toxicity of significant concern resides in a single isomer, the development of single isomer with the desired pharmacological effect would be desirable. 

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