Stereochemistry in Drug Action

Introduction:

Most biological molecules (proteins, sugars, drugs, etc.) are present in only one of many?chiral?forms, so different enantiomers of a?chiral drug?molecule bind differently (or not at all) to target?receptors. One enantiomer of a drug may have a desired beneficial effect while the other may cause serious and undesired side effects, or sometimes even beneficial but entirely different effects.?Advances in industrial chemical processes have made it economical for pharmaceutical manufacturers to take drugs that were originally marketed as a racemic mixture and market the individual enantiomers, either by specifically manufacturing the desired enantiomer or by?resolving?a?racemic mixture (Fig1).

On a case-by-case basis, the?U.S. Food and Drug Administration?(FDA) has allowed single enantiomers of certain drugs to be marketed under a different name than the racemic mixture.?Also case-by-case, the United States Patent Office has granted patents for single enantiomers of certain drugs. The regulatory review for marketing approval (safety and efficacy) and for patenting (proprietary rights) is independent, and differs country by country.

Fig.1; Racemic Mixture.

Importanc:

Selectivity?is a very important part of organic synthesis. In scientific papers regarding synthesis, selectivity is often listed in data tables alongside percent yield and other reaction conditions. While selectivity is deemed important in scientific literature, it has been challenging to effectively implement selectivity in drug development and production. A major issue with selectivity in?pharmaceuticals?is that a large percentage of drug syntheses by nature are not selective reactions, racemic mixtures are formed as the products. Separating racemic mixtures into their respective enantiomers takes extra time, money, and energy. One way to separate enantiomers is to chemically convert them into species that can be separated: diastereomers.?

Diastereomers, unlike enantiomers, have entirely different physical properties—boiling points, melting points, NMR shifts, solubilities—and they can be separated by conventional means such as?chromatography?or?recrystallization. This is a whole extra step in the synthesis process and not desirable from a manufacturing standpoint.?As a result, a number of pharmaceuticals are synthesized and marketed as a racemic mixture of enantiomers in cases where the less-effective enantiomer is benign. However, by identifying and specifically purifying the enantiomer which effectively binds to its respective?binding site?in the body, less of the drug would be needed to achieve the desired effect.?With the improvement of chiral technology, a rich repertoire of enantioselective chromatographic methods have become available for the separation of drug enantiomers on the analytical,?preparative,?and industrial scales.

Criteria:

According to the FDA, the stereoisomeric composition of a chiral drug should be known, and its effects should be well-characterized from pharmacologic, toxicologic, and clinical standpoints. In order to profile the different stereoisomers of enantiopure drugs, manufacturers are urged to develop quantitative assays for individual enantiomers in?in vivo?samples early in the development stage.

Ideally, the main pharmacologic activities of the isomers should be compared in?in vitro?systems in animals. During instances when toxic findings are present beyond the natural extensions of the pharmacologic effects of the drug, toxicologic evaluation of the individual isomers in question must be completed.

PHARMACOLOGY

The body with its numerous homochiral compounds being amazingly chiral selector, will interact with each racemic drug differently and metabolize each enantiomer by a separate pathway to generate different pharmacological activity. Thus, one isomer may produce the desired therapeutic activities, while the other may be inactive or, in worst cases, produce undesired or toxic effects .

In pharmacology area, only racemic drugs will be examined and their activity can be divided into three main groups. The majority of racemic pharmaceuticals have one major bioactive enantiomer (called eutomer), the other is inactive or less active (distomer) or toxic or can exert other desired or undesired pharmacological properties. The second category is intended to drugs where the two enantiomers are equally active and have the same pharmacodynamics. The last one is racemic drugs having only one eutomer, but the distomer could be transformed in body into its bioactive antipode by chiral inversion .

Group 1. Racemic drugs with one major bioactive enantiomer

In this group, there are a number of cardiovascular drugs, agents widely used for the treatment of hypertension, heart failure, arrhythmias, and other diseases. Among these are the β-adrenergic blocking agents, calcium channel antagonists and angiotensin-converting enzyme (ACE) inhibitors.

Levorotary–isomer of all β-blockers is more potent in blocking β-adrenoceptors than their dextrorotary-isomer, such as S(-)-propranolol is 100 times more active than its R(+)-antipode. A number of β-blockers are still marketed as racemic form such as acebutolol, atenolol, alprenolol, betaxolol, carvedilol, metoprolol, labetalol, pindolol, sotalol, etc, except timolol and penbutolol are used as single l-isomer. However, it has been demonstrated that d,l- and d-propranolol can inhibit the conversion of thyroxin (T4) to triiodothyronin (T3), contrary to its l-form. Therefore, single d-propranolol might be used as a specific drug without β-blocking effects to reduce plasma concentrations of T3 particularly in patients suffering from hyperthyroidism in which racemic propranolol cannot be administered because of contraindications for β-blocking drugs. It is to know that for a racemic drug, each enantiomer possesses its own pharmacological activities that can be null, similar, different or opposite.

Many calcium channel antagonists are used under racemic form such as verapamil, nicardipine, nimodipine, nisoldipine, felodipine, mandipine etc, except diltiazem is a diastereoisomer with two pairs of enantiomers. For example, the pharmacological potency of S(-)-verapamil is 10-20 times greater than its R(+)-antipode in terms of negative chromotropic effect on AV conduction and vasodilatator in man and animals. On the other hand, verapamil has another possible application in cancer chemotherapy as a modifier of multidrug resistance. Unfortunately, for this purpose, verapamil must be used at high concentrations leading to high cardiotoxicity. However, it was later found that R(+)-verapamil has far less cardiotoxicity than S(-)-verapamil. Therefore, the R-enantiomer would be preferable as a modifier of multidrug resistance in cancer chemotherapy, while the S-enantiomer or the racemate would be preferable as a calcium channel blocker for cardiovascular therapy.

All ACE inhibitors such as captopril, benazepril, enalapril, idapril are chiral compounds under diastereoisomeric form and most of them are marketed as single isomer. Valsartan, an angiotensin II receptor antagonist, is used as a single S-enantiomer and the activity of the R-enantiomer is clearly lower than the S-enantiomer.

Albuterol (salbutamol), salmeterol and terbutaline are sympathomimetic drug-selective β2-adrenoceptor agonists mainly used as bronchodilators in the treatment of asthma. They are longtime marketed as racemate. Pharmacologically, only their l-isomer or R (-)-isomer is effective and the other inactive d-or S (+)-isomer may be responsible for the occasional unpleasant side-effects associated with the drug. The Food and Drug Administration recently approved a chiral switch drug, levalbuterol (the pure l-isomer of albuterol) as a preservative-free nebulizer solution. However, some clinical studies recently reported that it is neither safer nor more effective than a same dose of racemic albuterol. In contrast, levalbuterol may cost as much as 5 times more than its racemate .

Methadone, a central-acting analgesic with high affinity for μ-opiod receptors, has been used to treat opiate dependence and cancer pain. Methadone is a chiral synthetic compound used in therapy under racemic mixture. In humans, R (-)-methadone is about [25-50] fold more potent as an analgesic than its S (+) antipode .

The list of racemic drugs with one eutomer is long. It includes anticonvulsants such as mephenytoine, ethosuximide; antiarrhythmics and local anesthetics such as propafenone, disopyramide, prilocaine, tocainide; antibiotics such as ofloxacin, moxalactam; anticoagulants such as warfarine, acenocoumarol; antihistaminics such as terfenadine, loratadine; antihyperlipidemic such as atorvastatin; psychostimulants such as amphetamine, metamphetamine; proton pump inhibitors such as omeprazole, pantoprazole, lansoprazole, etc . Some of these racemates recently undergo chiral switch to single enantiomer such as levofloxacin (from ofloxacin), levalbuterol (from albuterol), escitazolam (from citalopram), esomeprazole (from omeprazole), dexketoprophen (from ketoprophen), dexmethylphenidate (from methylphenidate), etc.

Group 2. Racemic drugs with equally bioactive enantiomers

There are only some racemic drugs that could belong to this group such as cyclophosphamide (antineoplastic), flecainide (antiarrhythmic), fluoxetine (antidepressant) .

Group 3. Racemic drugs with chiral inversion

There are two kinds of drug chiral inversion: unidirectional and bidirectional inversion .

Unidirectional enzyme mediated inversion was previously described only with 2-arylpropionate nonsteroidal anti-inflammatory drugs (NSAID), namely ibuprofen, ketoprofen, fenprofen, benoxaprophen, etc. For this group, only S-enantiomer is active i.e. has an analgesic and anti-inflammatory effect. For example, S-ibuprofen is over 100-fold more potent as an inhibitor of cyclooxygenase I than (R)-ibuprofen. In the body, only inactive R-enantiomer can undergo chiral inversion by hepatic enzymes into the active S-enantiomer and not vice-versa .

Bidirectional chiral inversion or racemization should be represented by 3-hydroxy-benzodiazepines (oxazepam, lorazepam, temazepam) and thalidomide in which R and S enantiomer can racemize?in vitro?by aqueous solution. However,?in vivo?this phenomenon could occur with thalidomide, but not with hydroxyl-benzodiazepines because of the differences in substituents around their chiral carbon. Some authors have found for the first time the difference in R- and S-oxazepam concentrations in treated rabbit serum. They explained that the chiral inversion by tautomerization of oxazepam cannot occur?in vivo?because each enantiomer is transported by protein (albumin) with different affinity. The binding affinities of the enantiomers to albumin may inhibit the attack of hydroxyl ions (water) and thus retard the epimerization and racemization?in vivo. Therefore, R- and S-oxazepam concentrations can be found different in the serum of these treated rabbits. On the other hand, He?et al? have also demonstrated that the?in vitro?chiral inversion of these benzodiazepine enantiomers was temperature-dependent and was inhibited by lowering temperature of aqueous solution to about 10°C . The S (+)-oxazepam enantiomer is 100-200 fold more potent as a tranquilizer and sedative than R (-)-oxazepam .

Toxicology

Enantiomeric selection to improve therapeutic effects or reduce drug toxicity has had mixed results in drug growth. Stereo selective metabolism of chiral compounds may also affect pharmacokinetics, pharmacodynamics, and toxicity, complicating genetic polymorphisms in drug disposition. Racemization of optically pure pharmaceuticals may occur in vivo, negating single enantiomer benefits or causing unexpected side effects. For therapeutic advantage and to minimize adverse events, appropriate chiral antidotes must be chosen. Carcinogenicity and teratogenicity can vary between enantiomers. Environmental toxicology provides several examples in which compound bioaccumulation, persistence, and toxicity show chiral dependence. In forensic toxicology, chiral analysis has been applied to illicit drug preparations and biological specimens, with the potential to assist in determination of cause of death and aid in the correct interpretation of substance abuse and “doping” screens.

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10.Chiral Drugs: An Overview Lien Ai Nguyen,1?Hua He,2?and?Chuong Pham-Huy3