How Does Stereochemistry Impact Drug Design?
Isomerism is extremely important in the field of clinical pharmacology and pharmacotherapeutics, as isomers differ in their pharmacokinetic and pharmacodynamic properties [1]. Pharmacokinetic differences are evident in varying levels of absorption and metabolism of different enantiomers, while pharmacodynamic differences can be seen in the differing pharmacological activity and potency.
Enantiomers of a chiral drug have identical physical and chemical properties in an achiral environment. However, in a chiral environment, one enantiomer may display different chemical and pharmacologic behavior than the other enantiomer. Because living systems like the human body are themselves chiral, each of the enantiomers of a chiral drug can behave very differently in vivo [2]. In other words, the R-enantiomer of a drug will not necessarily behave the same way as the S-enantiomer of the same drug when taken by a patient. For a given chiral drug, it is thus appropriate to consider the 2 enantiomers as 2 separate drugs with different properties.
As the 2 enantiomers of a chiral drug may differ significantly in their bioavailability, rate of metabolism, metabolites, excretion, potency and selectivity for receptors, transporters and/or enzymes, and toxicity, drugs that are a racemic mixture of both enantiomers must be carefully designed [2]. This is because one enantiomer may be responsible for the therapeutic effects of a drug whereas the other enantiomer is inactive and/or contributes to undesirable effects, as elaborated in the next section.
Currently, 56% of the drugs currently in use are chiral molecules and 88% of the last ones are marketed as racemates, consisting of an equimolar mixture of two enantiomers. Hence, it is extremely important that we are aware of the physiological effects that each enantiomer have on our bodies to prevent unwanted side effects. This has also sparked demand in developing synthesis pathways to develop optically pure products and methods to preserve enantiopure mixtures such that they do not racemize.
Not to worry, the scientific community has become increasingly aware of the potentially disparate effects that enantiomers can have in the human body. The drug discovery process is now putting much more focus in investigating the effects of the enantiomers and ways to minimize potentially harmful side effects when the drug is consumed. Thus, you need not be doubtful the next time your doctor prescribes medication for you as current drugs are undergoing the process of being investigated to determine if there are potentially unknown side effects due to the enantiomer of the drug.
In conclusion, drug isomerism has opened a new era of drug development. Our knowledge of isomerism has helped us in introducing safer and more effective drug alternatives of the newer as well as existing drugs.
References
- Chhabra, N., M.L. Aseri, and D. Padmanabhan, A review of drug isomerism and its significance. International journal of applied & basic medical research, 2013. 3(1): p. 16-18.
- McConathy, J. and M.J. Owens, Stereochemistry in Drug Action. Primary care companion to the Journal of clinical psychiatry, 2003. 5(2): p. 70-73.