(4.135); fen valerate

Some examples of the use of single isomers versus racemic mixtures of relatively "old" compounds in the clinic are also known, e.g. D-penicillamine and L-dopa (4.64). The use of both these compounds as pure enantiomers, rather than their racemates, resulted in a decrease in toxicity. The initial use of racemic dopa for the treatment of Parkinson's disease resulted in nausea, vomiting, anorexia, involuntary movements and granulocytopenia. The use of L-dopa resulted in halving the required dose, a reduction in toxicity, granulocytopenia was not observed with the single enantiomer, and an increased number of improved patients. Similarly the use of synthetic racemic penicillamine in the USA for the treatment of Wilson's disease resulted in a number of adverse reactions including nephrotic syndrome, optic neuritis, thrombocytopenia and/or leukopenia and the racemate was withdrawn. In the UK, D-penicillamine was obtained by the hydrolysis o

(4.138); thalidomide

of penicillin and the adverse effects were either reduced or abolished. Animal studies have also indicated that L-penicillamine inhibits growth with weight loss, causes intermittent fits and death, toxicity not observed with the D-enantiomer. Recent investigations have also indicated that the mutagenic activity of L-penicillamine is approximately eight fold greater than that of the D-enantiomer.

Thalidomide (4.138) is a compound frequently cited, particularly in the popular press, to support arguments for the development of single isomer drugs. Thalidomide was introduced, as the racemate, into therapeutics in the early 1960s as a sedative-hypnotic agent and was used in pregnant women for the relief of morning sickness. However, the drug was withdrawn when it became apparent that its use in pregnancy was associated with malformations, particularly phocomelia (shortening of the limbs), in the offspring. Investigations in the late 1970s using SWS mice indicated that both isomeric forms of the drug are hypnotic agents but that the teratogenic properties of the drug reside in the S-enantiomer. Thus, the argument goes: if the drug had been used as the single A-enantiomer then the tragedy of the early 1960s could have been avoided.

However, the situation with thalidomide is much more complex. Rodents are resistant to the teratogenic toxicity of the drug and the mouse is a poor model for teratogenicity testing. Data obtained in a more sensitive test species, New Zealand White rabbits, indicates that both the enantiomers of thalidomide are teratogenic. An additional problem with the drug is its stereochemical stability since the single isomers undergo rapid racemisation in biological media. Thus, even if a single isomer was administered to an experimental animal the other would be formed relatively rapidly. The acute toxicity of thalidomide, as determined by the LD50 test, also presents a complex problem. The individual enantiomers have similar reported LD50 values of approximately 1.0-1.2 g/kg in mice, but the value for the racemate is greater than 5 g/kg, i.e. the racemate is non toxic. In this case it would appear that the administration of the racemic mixture is exerting a protective effect the mechanism of which is unknown.

Taken together the above information indicates that the situation with thalidomide is by no means as clear as sometimes implied and the drug is certainly not a good example to cite in support of arguments for single isomer drugs.

A number of chiral drugs administered as racemates have been withdrawn from use, e.g. the cardioselective ß-blocker practolol, the NSAID benoxaprofen, the anticholinergic calcium antagonist terodiline. In the majority of cases the significance of stereochemistry to the adverse reactions is difficult to assess as the information is not available. However, the use of single isomers would have halved the required dose and the adverse reactions may have been reduced as a consequence.


As pointed out in the Introduction drug chirality has become a significant consideration for both the pharmaceutical industry and the regulatory authorities. Should all chiral drugs be marketed as single isomers? There are a number of arguments in favour of this approach, e.g. the plasma-concentration-effect relationships are simplified; the pharmacokinetic profile is less complex; there is a reduced potential for complex drug interactions; removal of a potentially interacting or toxic "impurity" resulting in an improved pharmacological profile of the drug and the potential for an increase in therapeutic index. The single enantiomer versus isomeric mixture debate will obviously have a considerable impact on new drug development and there is already evidence which indicates that the number of single isomer drugs/products being presented to the regulatory authorities is increasing. In the late 1980s the US Food and Drug Administration (FDA) issued a statement to the effect that "the Agency is impressed by the possibility that the use of single enantiomers may be advantageous by permitting better patient control, simplifying dose-response relationships and by reducing the extent of interpatient variation in drug response". Both the FDA and the European Union Committee on Proprietary Medicinal Products (CPMP) have issued formal guidelines for the investigation of chiral active substances, as have authorities in Switzerland, Australia and the Nordic Countries. In Japan no formal guidelines have been issued but stereochemical matters are dealt with via a normal consultation procedure.

At present none of the regulatory bodies have an absolute requirement for the development of single isomer drugs; however if a racemate is presented for evaluation then its use must be justified. There are a number of arguments which may be used to support the submission of a racemate:

1) the individual isomers are stereochemically unstable and readily racemise in vitro and/or in vivo;

2) the preparation of the drug as a single enantiomer on a commercial scale is not technically feasible;

3) the individual enantiomers have similar pharmacological and lexicological profiles;

4) one enantiomer is known to be totally inactive and not provide an additional body burden or influence the pharmacokinetic properties of the other;

5) the use of a racemate, or non-racemic mixture of isomers, produces a superior therapeutic effect than either individual enantiomer.

An additional valid question is the therapeutic significance of the compound in relation to the seriousness of the disease state and drug adverse reaction profile.

In addition to new drug development a number of established drugs, marketed as racemates, have been examined to see if their adverse reaction profile may be improved if used as single stereoisomers. This so-called "Racemic Switch" has at present resulted in a small number of compounds being re-marketed as single isomer preparations in some countries, e.g. the anorectic agent dexfenfluramine in Europe, the antimicrobial agent levofloxacin in Japan (currently undergoing Phase III clinical trials in Europe and the USA) and the NSAIDs dexibuprofen in Austria and dexketoprofen in Spain. In the case of dexfenfluramine (4.139) the racemate had been available for over 25 years and a considerable amount of clinical data had been accumulated. In terms of the pharmacology of the compound, (+)-(^-fenfluramine (4.139) has between four to five times greater

activity than the R-enantiomer in terms of serotonin receptor activity and reduction in food intake with only twice the toxicity in acute screening tests. However, the Renantiomer does exhibit side effects and it was possible to demonstrate an improved risk-benefit ratio with the single isomer compared to the racemate.

The most recently introduced (1996) single isomer drug in the UK is cisatracurium besylate, the 1R, 2R, 1'R, 2'R-isomer (4.140) of the non-depolarizing neuromuscular blocking agent atracurium (4.5). Atracurium contains four chiral centres but due to its symmetrical structure exists as ten isomeric forms. The commercially available material consists of an unequal parts mixture of the ten forms of which the 1R, 2R, 1'R, 2'R-isomer accounts for 15% of the material. The single isomer has similar pharmacodynamic properties to atracurium in terms of onset, duration and recovery of action, with an improved side effect profile with respect to cardiovascular effects and histamine release.

Other compounds under examination as racemic switches include the P-blocker sotalol, the antiarrhythmic verapamil and the anaesthetic-analgesic agent ketamine. However, additional compounds presented in alternative formulations allowing different routes of drug administration will probably be marketed in the near future. The resurgance of interest in drug chirality has also indicated other agents which may be candidates for the racemic switch. For example (R^-salbutamol (4.141) is 68 times more active than the S-enantiomer as a p2-agonist. Recent reports indicate that the S-enantiomer induces airway hyper-reactivity and may cause adverse effects in asthmatic patients and thus


(4.14A); tisatracuriuni be sy late

(4.14A); tisatracuriuni be sy late

(4.141); (R) - salbutamol

salbutamol may be considered for racemic switch to the single A-enantiomer. That such reintroductions of single isomer drugs may not be without problems and may provide unexpected results is illustrated by the example of labetalol/dilevalol referred to previously (Section 4.6.2). In the case of labetalol removal of the isomeric "impurity" was not a trivial matter.


The material presented in this chapter was selected to provide a background to the biological significance of drug chirality and to highlight the advantages of stereochemical considerations in pharmacology. In the past such quotes as "Warfarin enantiomers should be treated as two drugs" and " (S) and ^-propranolol are essentially two distinct entities pharmacologically" have appeared in the literature. In the future, as a result of regulatory considerations, the majority of chiral drugs will be introduced as single isomers and a number of compounds currently marketed as racemates will be introduced as single isomers. But for many drugs, currently in use as racemates, relatively little is known regarding the pharmacological or toxicological activities or pharmacokinetic properties of the individual enantiomers. For example there is little published information concerning the effect of novel formulations on enantiomer delivery or bioavailability; the influence of ageing, disease state, gender, or genetic factors on drug enantiomer disposition; the influence of drug interactions with respect to stereoisomers. The results of additional pharmacological and pharmacokinetic investigations of the enantiomers of marketed racemates may result in new indications for "old" drugs, improve the clinical use of these agents and hence result in increased safety and efficiacy. Probably the best take home message for the budding medicinal chemist would be: if you make a chiral compound, finish the job and separate the isomers yourself don't expect the patient to do it for you.


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