Chirality is widespread in nature and is fundamental to life. It arises from straightforward geometry - any object that lacks inverse symmetry can exist in two distinguishable mirror images, called enantiomers. For example, our hands are chiral: the right hand is an enantiomer of the left hand, and neither can be superimposed on the other by translation or rotation.
By the beginning of the 20th century examination of the role of chirality in drug action and disposition had begun and enantioselectivity was observed in many cases. In 1933 Easson and Stedman proposed a fundamental model as the basis for enantioselective drug-receptor interactions.
The three-point-intreraction model, originally proposed for a specific effect of epinephrine was later broadened to explain biological enantioselectivity of chiral drugs in general, be it in drug-receptor interactions, enzyme-substrate interactions, protein binding, etc. Further, the three-point-interaction model of enantioselectivity has also been used in chromatography to explain the chiral distinction between the chiral analyte molecules with the chiral stationary phases.
With the advance in organic chemistry in the early decades of the century the more complex drugs began to yield their chemical structures. For example, the structure of morphine was proposed in 1923. The drug was synthesized in 1952 and its absolute configuration was determined in 1955. (+)-Morphine was synthesized in 1960 and was shown to differ significantly from the natural (-)-morphine in that it lacks analgesic activity. In 1951 Bijovet et al. determined the absolute configuration of sodium rubidium tartrate using X-ray scattering technique. This milestone in stereochemistry opened the door to the elucidation of the absolute stereochemistry of thousands of compounds, including many drugs.
Chirality continued to engage pharmacologist and chemists during the reminder of the century. Enantioselectivity in the effects or disposition of chiral drugs was found in a large number of cases, for a large variety of pharmacological effects and chemical structures. Examples of enantioselective toxicity were also observed, for example levodpa. Initial trial in the 1960s for the treatment of Parkinson’s disease used racemic mixture but it became clear that unacceptable toxicity was present in the D-enantiomer and the drug was therefore developed in the enantiopure, L-form.
By the 1970s a large body of information has accumulated on the role of chirality in drug action and disposition and many reviews and monographs on the subject appeared during the last ca. 30 years of the century. Modern pharmacotherapy came of age during the 20th century. Many new pharmacologically active natural products were isolated and identified thousands of new compounds (many of them chiral) were synthesized and examined for pharmacological effects and therapeutic potential. By 1987 nearly 55 per cent of all clinically used drugs were based on chiral molecules. Many of the new chiral drugs introduced were natural products or semi- synthetic derivatives and were introduced in the enantiopure forms.
Table 1 lists some recently launched drugs derived from natural products.
With time, entirely synthetic chiral drugs began to dominate a major segment of the new therapeutic agents and were marketed as racemates. In this context it is pertinent to point out that some racemic drugs were withdrawn from the world market due to stereochemically induced toxicity. Table 2, presents a list of selected drugs that have been withdrawn from the market based on stereochemical issues.
One may wonder whether in such cases the adverse effects in question may be enantioselective, i.e. whether a unichiral version (that excludes the more toxic enantiomer, the distomer) would have been a safer drug. It should be noted, however despite the inclination for the marketing of synthetic chiral drugs in the racemic form, a few synthetic chiral drugs were introduced in a unichiral form viz. (-)-timolol, D-Penicillamine, etc. It is evident that in most such cases the choice of developing a single enantiomeric form could be attributed to the severe toxicity exhibited by its mirror-image twin.
During most of the century,pharmaceutical companies did not show much interest in developing unichiral drugs if nature didn’t offer them. This lack of interest in chirality from the industry may have been the consequence of a light-handedness of government drug-regulatory agencies on issues pertaining to drug chirality. For instance, until 1987 the US FDA did not require for data on enantiomeric composition of chiral substances in new-drug application. In late 1980’s the stereochemically engineered drug toxicity and publications exposing the neglect and pre-pasture attitude in chiral drug research lead to the re-discovery of stereochemistry. This renewed awareness has created a new climate in chiral research leading to debate on the merits of enantiopure therapeutic agents vs. racemic mixtures as new drugs. A great deal of evidence accumulated in favour of the development of unichiral drugs, which provides cleaner pharmacological profile, less complicated plasma concentration-effect relationship and simpler pharmacokinetic profile.
The decision whether to be developed as single enantiomer or racemates is a complex issue and need to be judged from the merit of each case. It will require various inputs like pharmacokinetic, pharmcodynamic and toxicological profile of component enantiomer, distomer liability, tendency for chiral inversion, cost of production, market edge on the competitors, etc. There are instances where the unichiral form proved to be less safe than the racemate, e.g., labetalol, fluoxetine and sotalol.
FDA issued its guidelines governing the development of chiral drugs in 1992. In roughly the same period other regulatory agencies across the globe viz. European Union, Japan, Canada, Australia, etc. issued similar guidelines. Although the new regulations do not ban the introduction of new racemic therapeutics their overall effect is in fact the near-total disappearance of racemic substances as new drugs. Because of this majority of the new chiral drugs were marketed as single-enantiomer forms. The strong current trend towards enantiopure chiral drugs will also exert pressure on racemic therapeutics already on the market in the sense that a shift to a more potent or less toxic enantiomer could be well motivated from both medicinal and economical stand points. This is well reflected by the racemic switches on and near market [Table 3].
Today, chiral drugs are coming under the increasing scrutiny among pharmaceutical manufacturers, pharmacologists, pharmacokinetists, medicinal chemists, separation scientists, agronomists, entomologists, regulatory agencies and others. This is because the left-and right-handed twins of mirror-image molecules often behave differently from each other in bio-environment. For the very same reason, while pursuing scientific investigations (pharmacokinetic, pharmcodynamic or toxicologic) on handed-drugs, it is mandatory that the aspect under study be viewed from both sides of the mirror. Clearly the ultimate goal of all these scientific endeavours is higher quality medicines to make drug therapy more effective, specific and safer for the benefit of mankind.
- The author is Professor, Department of Pharmacy, Annamalai University