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Chirality in pharmaceutical research and development

Valliappan Kannappan & Mohan Sellappan
Wednesday, May 10, 2023, 08:00 Hrs  [IST]

In pharmaceutical research, chirality, or the ability of molecules to exist in two or more mirror-image forms, plays an important function. Numerous drugs are chiral, and their different enantiomers can have distinct pharmacological effects, making chirality a crucial consideration in pharmaceutical research. Enantiomers can interact differentially with the body's biological receptors, enzymes, and transporters, resulting in distinct pharmacokinetic and pharmacodynamic profiles. For a detailed treatment of chiral drugs readership may consult the page on “Chiral drugs” in Wikipedia [https://en.wikipedia.org/wiki/Chiral_drugs] and associated citations.

The importance of chirality in pharmaceutical research can be illustrated by the example of thalidomide. Thalidomide was a drug that was widely used in the 1950s and 1960s as a sedative and anti-nausea medication for pregnant women. However, it was later discovered that one enantiomer of thalidomide caused severe birth defects, while the other enantiomer was safe.

This tragedy led to increased awareness of the importance in drug development and testing. Also this incidence changed the way one look at mirror-image molecules. Today enantiomers are looked at as two chemical species are not two forms of the same molecule. In other words they are treated as a fixed drug combinations or as a polypharmacy.

The pharmaceutical industry has long recognized the importance of chirality in drug design, as it affects not only the efficacy of drugs but also their safety and tolerability. Chiral drugs are often more effective than their racemic counterparts (mixture of both enantiomers), as they can interact with specific molecular targets in the body with higher affinity and selectivity. For example, the antihistamine drug cetirizine contains a single stereogenic center and exists as a racemic mixture. However, the active enantiomer (levocetirizine) has increased potency and decreased side-effects than the inactive one (dextrocetirizine).

Chirality and biological activity
Chirality also plays a crucial role in pharmacokinetic, pharmacodynamic and toxicity profile of chiral drugs. Enantiomers can be metabolized differently in the body, leading to different rates and pathways of elimination. In some cases, the metabolites of one enantiomer can be more toxic than the leading to adverse effects.

A classical example of a chiral drug that demonstrate stereoselective metabolism is the bronchodilator Salbutamol (Albuterol). This drug is available as a racemic mixture. The (R)-Salbutamol is the eutomer, the enantiomer with the desired activity and the (S)-enantiomer is the distomer (the impurity or the activity which we are not looking for). In this case the (R)-salbutamol, gets metabolized faster than the (S)-enantiomer resulting in a drop in the biological activity. Table below depicts a brief list of chiral drugs that exhibits enantioselective toxicity.

The antitubercular agent Ethambutol contains two constitutionally symmetrical stereogenic centers in its structure and exists in three stereoisomeric forms. An enantiomeric pair (S,S)- and (R,R)-ethambutol, along with the achiral stereoisomer called meso-form, it holds a diastereomeric relationship with the optically active stereoisomers. The activity of the drug resides in the (S,S)-enantiomer which is 500 and 12 fold more potent than the (R,R)-enantiomer  and the meso-form. The drug s initially introduced for clinical use as the racemate and was changed to the (S,S)-enantiomer, as a result of optic neuritis leading to blindness. Toxicity is related to both dose and duration of treatment. All the three stereoisomers were almost equipotent with respect to side effects. Hence the use of (S,S)-enantiomer greatly enhanced the risk/benefit ratio.

Chirality is also essential to the development of novel pharmaceuticals. Drug discovery often involves screening large libraries of molecules for their biological activity against a specific target. Chiral molecules can have different activities against the same target, and their activities can vary depending on the target's conformation. Therefore, screening both enantiomers separately is essential to identify the most active and selective compounds.

Chirality and regulatory affairs
Currently, chirality is a major concern for both the pharmaceutical industry and regulatory agencies. Regulatory agencies, such as the Food and Drug Administration (FDA) of the United States, have mandated that pharmaceutical companies conduct distinct tests on both enantiomers of chiral drugs to ensure that they have similar pharmacokinetic and pharmacodynamic properties. The FDA has established guidelines for the development of chiral pharmaceuticals, which include the evaluation of pharmacokinetic and pharmacodynamic differences between enantiomers and the determination of the safety and efficacy of each enantiomer. This demand has increased chirality research and led to the development of novel technologies and techniques for the synthesis and analysis of chiral compounds.

Chiral synthesis, separation and analysis
One of the challenges of working with chiral compounds is that they can be difficult to synthesize, purify, and analyze. This is because enantiomers have the same chemical properties and are difficult to distinguish from each other, in an achiral environment, using conventional analytical methods such as high-performance liquid chromatography (HPLC). So, to analyze enantiomers one needs to create the right chiral environment where the enantiomeric differences are pronounced. In response, scientists have developed numerous techniques for the separation and analysis of enantiomers, such as chiral chromatography, chiral capillary electrophoresis, and chiral nuclear magnetic resonance spectroscopy.

Chiral chromatography is a widely used technique for the separation of enantiomers. It involves the use of a chiral stationary phase, which is a stationary phase that contains a chiral molecule that interacts selectively with one enantiomer. This results in the separation of the enantiomers based on their different interactions with the stationary phase. Some studies suggest that HPLC is the most widely employed tool for chiral separation and analysis (Francotte, Eric; Lindner, Wolfgang (2006). Chirality in drug research, p. 193, Wiley-VCH, ISBN 978-3-527-60943-7. OCLC 163578005).

Chiral switches
Chiral switch, a re-engineering approach, has enabled in the remarketing of a number of racemic drugs as chiral specific enantiomer products. Chiral switching strategy is the way most blockbuster drugs have entered the market as enantiopure drugs. But the alternate route is de novo synthesis of chiral specific drugs. The chiral switches may have the same, very similar, therapeutic indications as the original racemic drug. But, there are instances where           new indications for the old drug have been reported. A brief list of launched   chiral switches includes dexiburpofen, levofloxacin, esomeprazole, and levocetirizine. For a detailed treatment of chiral switches readership may consult the page on “Chiral switches” in Wikipedia [https://en.wikipedia.org/wiki/Chiral_switch] and references therein.

Chirality is a fundamental concept in pharmaceutical research with significant implications for drug development, efficacy, safety, and patent law. Understanding the chiral properties of a drug is essential for regulatory approval and patent protection. The ability to selectively target specific enantiomers can result in the development of safe and effective pharmaceuticals with fewer side effects. Therefore, chirality research is essential for advancing pharmaceutical research and enhancing patient outcomes.

(Author Valliappan Kannappan is Founder, chiralpedia.com and Professor Emeritus, Karpagam College of Pharmacy Coimbatore. Author Mohan Sellappan is Principal and Professor, Karpagam College of Pharmacy, Coimbatore)


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