Academic Supplement The Development of Si n g l e - I s o m e r M o l e c u l e s : Why and How By Andrew J. Hutt, PhD

ABSTRACT to know that their physician had just prescribed them two, Until relatively recently the three-dimensional nature of or possibly four, “drugs” rather than one. It may well sur- d r ug molecules has been largely neglected, with appro x i- prise them even more to find that their physician was mately 25% of marketed drugs being mixtures of agents u n a w a re of that fact and had not done so as a conscious rather than single chemical entities. These mixtures are not act for their therapeutic benefit. combinations of drugs but mixtures of stereoisomers, gener- These mixtures of “drugs” arise as a result of the use of ally racemates of synthetic . The individual racemates (an equal-parts mixture of a pair of enan- enantiomers present in such mixtures frequently differ in both tiomers), and other combinations of stereoisomers, rather their pharmacodynamic and pharmacokinetic profiles as a than single chemical entities of chiral drug molecules. result of stereochemical discrimination on interaction with The individual components of these mixtures fre q u e n t l y chiral biological macromolecules (enzymes and re c e p t o r s ) . d i ffe r in terms of their pharmacodynamic and pharm a c o- The use of such mixtures may present problems if their kinetic profiles and their use may present problems if adverse effects are associated with the less active stere o i s o m e r their adverse effects are either associated with the “inac- or do not show stere o s e l e c t i v i t y. In addition, interactions tive” isomer or do not show stereoselectivity. between enantiomers may occur such that the observed activ- In recent years, as a result of advances in methodology ity of the racemate is not simply the product of the effects of associated with stereoselective synthesis and stere o s p e - the individual enantiomers. Since the mid-1980s there has cific analysis of chiral drug molecules, together with the been an ongoing “racemate-versus-enantiomer” debate with i n c reasing realization of the potential significance of the the potential advantages of single-isomer products, including d i ff e r ential biological pro p e rties of stereoisomers, dru g i m p roved selectivity of action and potential increase in thera- s t e re o c h e m i s t r y has become a topical subject. The issue peutic index, being highlighted. As a result, re g u l a t o r y of stereochemistry has been examined in both the popular authorities have issued guidelines for dealing with chiral lay and scientific pre s s 2 - 7 with headlines such as: “Dru g molecules, and the number of single enantiomer agents pre- f i r ms sort their lefts from their rights.”5 In practically all sented for evaluation has increased. Racemic mixtures may such articles, the issue of drug stere o c h e m i s t r y is still be developed but re q u i re justification such that the risk- a d d ressed in fairly emotive terms, citing the example of benefit ratio may be assessed. In addition to new chemical the teratogen thalidomide (see below) as an instance entities, a number of “old” mixtures are being re-examined as w h e r e the use of a single stereoisomer would have pre- potential single-isomer products, the chiral switches, with vented the tragedy of the early 1960s. the potential for an improved therapeutic profile and possi- The magnitude of the stere o c h e m i s t ry problem in ther- bly new indications. However, for the majority of agents apeutics may be appreciated from a survey carried out in c u r rently marketed as mixtures, relatively little is known the 1980s of 1,675 dru g s . 8 Of these agents, 1,200 were c o n c e rning the pharmacological or toxicological pro p e rt i e s classified as synthetic, of which 480 were chiral with 58 of the individual enantiomers. being marketed as single stereoisomers (ie, approximately C N S S p e c t ru m s . 2002:7(suppl 1):14-22 25% of the agents examined were used as mixtures of s t e reoisomers). From these figures, it is obvious that dru g INTRODUCTION s t e r e o c h e m i s t r y is not associated with, or restricted to, p a rticular therapeutic groups of drugs but is an acro s s - “...the sad truth is that we still learn most of our chemistry the-board problem. in Flatland, to the detriment of our science.” – Sir John Cornforth (1981)1 The lack of knowledge of drug stere o c h e m i s t ry amongst physicians is probably not surprising for two main re a s o n s : Until relatively re c e n t l y, pharmacology has been a (1) the lack of readily available information concerning dru g Flatland science, the three-dimensional nature of dru g s t e r e o c h e m i s t r y in the sources that physicians utilize, molecules being largely neglected. In terms of therapeu- together with the associated complexity of stere o c h e m i c a l tics, the majority of patients would probably be surprised t e rminology; and (2) a physician could reasonably expect

D r. Hutt is lecturer in pharmaceutical chemistry in the Department of Pharm a c y, King’s College London, in London, England. D i s c l o s u re : This work was funded by Forest Pharmaceuticals, Inc. M e d Works Media 14 April 2002 Academic Supplement the pharmaceutical industry, together with the re g u l a t o ry a result of their helical stru c t u res (ie, the α-helix of pro t e i n s agencies, to provide them with the most appropriate mate- and the double helix of DNA) in the same way that a spiral rial available irrespective of stereochemical considerations. s t a i r case or corkscrew may have either a right- or left- H o w e v e r, with the advent of the so-called r a c e m i c or c h i r a l handed turn. In the case of the above examples both helices s w i t c h (see below), and the possibility that both single a r e right-handed. The stereochemical homogeneity of s t e reoisomer and preparations of a dru g n a t u r e was acquired very early in evolutionary time may be available at the same time, it is essential that the s c a l e s , 1 3 , 1 4 and as nature has made a pre f e rence in terms of p rescriber is aware of the nature of the material being used its stere o c h e m i s t ry it should not be surprising that enzymes ( m i x t u re or single compound) and to have an appreciation of and receptor systems almost always show a stere o c h e m i c a l the drug stere o c h e m i s t ry issue. p re f e rence for one or the other of a pair of enantiomers, and The fundamental aspects of stere o c h e m i s t ry, together that many of the natural ligands for these systems (eg, neu- with the associated terminology and nomenclature, have rotransmitters, hormones, endogenous , etc.) are been addressed by Dr. Gal (pages 8-13). This article will themselves single isomer chiral molecules. attempt to explain where and how discrimination between The diff e rential biological “activity” of stereoisomers is s t e reoisomers occurs in biological systems, together with the not a new phenomenon in spite of the considerable intere s t possible consequences of such discrimination and the cur- over the last two decades. In 1858, Pasteur showed that the rent re g u l a t o ry position with respect to chiral compounds. mould Penicillium glaucum metabolized (+)-tartrate more rapidly than the (-)-enantiomer. This was followed in 1886 BIOLOGICAL DISCRIMINATION by Piutti’s observation that the (+)-enantiomer of OF STEREOISOMERS asparagine had a sweet taste whereas (-)-asparagine was Enantiomers are pairs of stereoisomers that are related as i n s i p i d . 1 5 The diff e r ential pharmacodynamic activity of non-superimposable mirror images, and other than their d rug enantiomers was initially re p o rted in the early years of e ffect on the rotation of the plane of plane-polarized light, the last century by the British pharmacologist Cushny,1 6 have identical physicochemical pro p e rties (Figures 1 and who demonstrated diff e r ences in the activity of atro p i n e 2 ) . 9-12 As a result, diff e r ences between enantiomers are , and (-)-hyoscyamine and (-)- and (+)-adrenaline; Cushny under normal circumstances, difficult to detect. However, when placed in a “chiral environment” these diff e re n c e s become more marked. Biological systems at a molecular level are intensely chiral environments being composed of biopolymers (proteins, glycolipids, and polynucleotides) f rom the single stere o i s o m e r, or homochiral, building blocks of nature (L-amino acids and D-carbohydrates). In addition, some of these biological macromolecules exhibit as

FIGURE 2. STEREOISOMERS OF E s c i t a l o p r a m (R) - c i t a l o p r a m P H E N Y L P R O PA N O L A M I N E P h e n y l p r opanolamine (2-amino-1-phenylpropanol) contains two chiral centers in its stru c t u r e and four stereoisomers, ie, two pairs of enantiomers are possible. In this diagram, those FIGURE 1. INDIVIDUAL ENANTIOMERS OF compounds that are related horizontally (ie, the upper and C I TA L O P R A M lower pairs) are enantiomeric, whereas those which are re l a t e d In this diagram those chemical bonds at the chiral carbon v e r tically are diastereomeric. Diastereoisomers are stere o i s o- atom re p r esented by solid lines are re g a rded as being in the mers that are not enantiomeric, ie, are not mirro r- i m a g e - plane of the paper, those drawn as dotted lines project back related; they differ in their physicochemical pro p e r ties and away from the re a d e r, and those re p r esented by the wedge m a y, in principle at least, be separated relatively easily. The p r oject towards the re a d e r. The enantiomer on the left, enantiomeric pairs of compounds are also known by the trivial (S)-citalopram, given the generic name , is a names norpseudoephedrine (upper pair) and nore p h e d r i n e potent selective serotonin reuptake inhibitor which in in vitro (lower pair). Racemic norephedrine has recently been with- test systems is between 130- and 160-fold more potent than drawn (October 2000) in the US due to an association with the R-enantiomer (right).9 , 1 0 hemorrhagic stroke.11,12 Hutt AJ. C N S S p e c t r u m s . Vol 7, No 4 (suppl 1). 2002. Hutt AJ. C N S S p e c t r u m s . Vol 7, No 4 (suppl 1). 2002.

April 2002 15 M e d Works Media Academic Supplement went on to publish what is probably the first book devoted As pointed out above, stereoselectivity in drug action is to stereoisomerism in pharm a c o l o g y.1 6 not a new phenomenon, but apart from a relatively small The interaction between a drug and its target, a re c e p t o r number of cases, stere o c h e m i s t ry was to a large extent neg- or enzyme active site, is associated with bonding interac- lected during what was almost a “Golden Age” of drug dis- tions between the functionalities in the drug stru c t u re and c o v e r y and development between the 1950s and early c o m p l e m e n t a r y sites on the target macromolecule. Such 1970s. However, the idea of investigating single stere o i s o- interactions may have considerable steric constraints and, mers following either the “failure” of a racemic mixture or in the case of stereoisomers, the three-dimensional spatial the observation of unacceptable adverse effects with a mix- a rrangement of the groups in the drug molecule are of con- t u re is not new. siderable significance. Penicillamine, introduced originally for the treatment of Easson and Stedman1 7 in 1933 rationalized the diff e r- Wi l s o n ’s disease,2 3 has been used in rheumatology for a ential pharmacodynamic activity between enantiomers, number of years. It was introduced as a synthetic racemate p roposing a dru g - receptor interaction model in which the in the United States and subsequently withdrawn as a re s u l t m o re active enantiomer takes part in a minimum of thre e of optic neuritis.2 4 The single stere o i s o m e r, D-penicillamine, simultaneous intermolecular interactions with the re c e p- obtained by the hydrolysis of penicillin, was used in the tor surface, whereas the less active enantiomer interacts United Kingdom and the adverse effect was not re p o rted at at two sites only (Figure 3). Thus, the “fit” of the individ- that time.2 5 , 2 6 S i m i l a r l y, the initial use of racemic dopa for ual enantiomers to the receptor surface differs, as does the treatment of Parkinson’s disease resulted in nausea, the energy of the interaction. The Easson-Stedman model vomiting, anorexia, involuntary movements, and granulocy- is a useful but simplistic representation as the interaction topenia. The use of L-dopa resulted in halving the re q u i re d of the drug with a receptor, or enzyme active site, is likely dose, a reduction in adverse effects, the granulocytopenia to result in conformational changes in both the drug and not being observed with the single enantiomer, and an receptor macromolecule. The chiral recognition pro c e s s i n c reased number of improved patients. continues to be a matter of considerable interest. In That stereoisomers are and should be re g a rded as diff e r- recent years, alternative models and refinements to exist- ent compounds rather than as diff e rent forms of the same ing models have been proposed.18,19 compound is emphasized on examination of their biological p ro p e rties. Individual stereoisomers may have similar activ- STEREOSELECTIVITY IN PHARMACODYNAMICS ities or differ either quantitatively or qualitatively. However, The diff e r ential pharmacodynamic activity of dru g it is the exception that the re q u i r ed pharm a c o d y n a m i c s t e r eoisomers has given rise to additional term i n o l o g y. activity resides in a single stereoisomer with its enantiomer Thus, the stereoisomer with the greater activity, or re c e p t o r being biologically inert. Similarly, there are few examples a ff i n i t y, is termed the eutomer, while that with the lower w h e re the re q u i red activity resides in a single stere o i s o m e r activity or affinity is known as the distomer.2 0 , 2 1 The ratio of activities, a measure of the stereoselectivity of the system under examination, is known as the Eudismic Ratio.2 0 These designations, and the Eudismic Ratio, refer to one biological activity only, and for a dual-action drug the eutomer for one activity may be the distomer for the other. Examples are also known in which the pharm a c o d y n a m i c activity of a pair of enantiomers is so diff e rent that they are marketed with diff e r ent therapeutic indications. Both enantiomers of propoxyphene are available, the dextro - and levoro t a t o ry enantiomers being used as an and antitussive, respectively (2R, 3S- d e x t ro p ro p o x y p h e n e , A B D a r von; 2S, 3 R- l a e v o p r o p r oxyphene, Novrad; the trade names also being mirro r-image related). This situation also occurs with other agents in the FIGURE 3. BIOLOGICAL DISCRIMINATION BETWEEN g r oup, a fact which has not escaped the popular novelist A PAIR OF ENANTIOMERS Patricia Cornwell. In her novel, Body of Evidence, one of the The enantiomer on the left (A) takes part in three complemen- characters dies with a bottle of the antitussive, dextro m e t h o r- t a ry interactions with the receptor site, whereas that on the phan, at the bedside. Toxicological analysis “confirms” the right (B) interacts at two sites only. Alternative orientations of p resence of the drug in the body but only later in the novel, the enantiomer on the right to the active site are possible, but only two interactions may take place at any time. The vert i c a l following examination of the isolated material using optical line re p resents a mirror plane where the center stru c t u re is the rotation, does it become apparent that the material consumed reflection of that on the left. is in fact the potent analgesic and that the Hutt AJ. C N S S p e c t r u m s . Vol 7, No 4 (suppl 1). 2002. character in fact committed suicide.2 2

M e d Works Media 16 April 2002 Academic Supplement and the adverse effects, or toxicity, reside solely in the enan- tion of the L- compared to the D-enantiomers of dopa3 6 t i o m e r. A number of possible situations may arise on com- and methotre x a t e 3 7 , 3 8 has been re p o rted. Such pro c e s s e s , parison of the pharmacodynamic pro p e r ties of individual in theory at least, may be expected to increase the rate s t e reoisomers, which are summarized together with appro- rather than the extent of absorption. priate examples in Table 1. In drug metabolism, stere o d i f f e rentiation is the ru l e rather than the exception, and stereoselective metabo- STEREOSELECTIVITY AND lism is probably responsible for the majority of the diff e r- DRUG DISPOSITION ences observed in enantioselective drug disposition.3 5 S t e r eoselectivity is also observed in drug disposition, The individual enantiomers of a drug may underg o p a r ticularly for those processes which depend upon a metabolism via diff e rent routes to yield diff e r ent pro d- direct interaction between the drug and a chiral biological ucts and are frequently metabolized at diff e r ent rates. m a c romolecule (eg, active transport processes, binding to S t e r eoselectivity in drug metabolism may arise as a plasma and tissue proteins, and drug metabolism).32-35 result of diff e rences in binding of the enantiomeric sub- Tr a n s p o r t of the majority of drugs through biological strates to the enzyme active site and/or be associated membranes occurs by passive diffusion, a process which with catalysis due to diff e rential reactivity and orienta- is dependent upon physicochemical pro p e r ties (ie, tion of the target groups to the catalytic site. 3 9 l i p o p h i l i c i t y, pKa, and molecular size). Since enan- S t e reoselectivity may also occur in renal clearance as a tiomers have identical physicochemical pro p e rties, stereo - result of either selectivity in protein binding and/or tubu- selectivity is not expected, but diff e r ences between lar secretion or uptake.4 0 d i a s t e r eoisomers may well occur as a result of diff e re n - As a result of stereoselectivity in the above processes, the tial solubility. However, in the case of compounds trans- p h a rmacokinetic profiles of the individual enantiomers of a p o r ted via carr i e r-mediated mechanisms (eg, facilitated d r ug administered as a racemate may differ markedly. d i f fusion or active transport, processes requiring an P h a rmacokinetic parameters (eg, clearance, volume of dis- interaction between a substrate and carrier macro m o l e - tribution, half-life, etc) and pharm a c o d y n a m i c / p h a rm a c o k i- cule), stereoselectivity is expected. Pre f e rential absorp- netic relationships derived from the determination of “total” d rug concentrations (the sum of the two enantiomers pre s e n t in bioanalytical samples) are of limited value and poten- TABLE 1. STEREOISOMERS AND 4 1 , 4 2 PHARMACODYNAMIC COMPLEXITY2 7 - 3 1 tially highly misleading. In comparison to the diff e r ences observed between stereoisomers in terms of their pharmacodynamic activity, 1. Activity resides in a single stereoisomer eg (S)-α–methyldopa (antihypertensive) the magnitude of the diff e r ences in pharm a c o k i n e t i c 2. Enantiomers have similar pharmacodynamic activity parameters tends to be fairly modest, generally between 3 3 eg flecainide (antiarrhythmic) 1- to 3-fold. H o w e v e r, the degree of stere o s e l e c t i v i t y promethazine (antihistamine) o b s e r ved for a particular pharmacokinetic parameter is 3. Both enantiomers marketed with different also influenced by the organizational level that the indications parameter re p r esents. For example, pharm a c o k i n e t i c eg (analgesic) parameters may be divided into three levels of org a n i z a- levopropoxyphene (antitussive) tion: macromolecular—intrinsic formation clearance of 4. Enantiomers have opposite eff e c t s metabolites (CL ), fraction unbound in plasma (fu); eg picenadol ( analgesic) f int (+)-(3S,4R)–picenadol, µ–receptor o rgan—hepatic metabolic clearance (CLH), renal clear- (-)-(3R,4S)–picenadol, µ– ance (CLR); and whole body (systemic clearance, volume (±)-picenadol, partial agonist of distribution, and half-life).3 4 Thus, whole body parame- 5. One enantiomer antagonizes the side effects of ters are determined by multiple organ parameters, which the other in turn are a reflection of multiple macromolecular inter- eg indacrinone (loop diuretic) actions, which in the case of a pair of stereoisomers may (R)-indacrinone, diuretic be either amplified or attenuated with each level of organ- (S)-indacrinone, uricosuric ization. For example, in the case of verapamil, the ratio 6. Required activity resides in one or both enantiomers, adverse effects predominantly S/R of the half-lives of the individual enantiomers is rela- associated with one stereoisomer tively modest at 1·17:1, reflecting the whole body level of eg (S)- more potent anaesthetic and analgesic o r ganization and dependence on volume of distribution than the R-enantiomer, which causes a greater (S / R 2·34:1) and clearance (S/R 1·77:1). However, exami- incidence of emergence reactions (hallucinations nation of the metabolite formation clearance for demethy- and agitation) lation, a macromolecular parameter, yields a S / R ratio of See references 27-31 and references cited in the text for additional infor- mation and further discussion of the possible scenarios that may arise. 33:1. Thus, in the case of verapamil, the modest ratio in Hutt AJ. C N S S p e c t r u m s . Vol 7, No 4 (suppl 1). 2002. half-life masks the significant enantioselectivity of the metabolic pathways.34

April 2002 17 M e d Works Media Academic Supplement

SIGNIFICANCE OF relatively little is known with respect to the influence of STEREOCHEMICAL CONSIDERATIONS route of administration, formulation, drug interactions, age, The majority of chiral drugs are used as racemates g e n d e r, disease state, pharmacogenetics, and race on the rather than as single stereoisomers. While there has been disposition and resultant pharmacodynamic effects of the considerable interest in drug stere o c h e m i s t r y in re c e n t individual enantiomers of racemic drugs. Repre s e n t a t i v e years, for the vast majority of these mixtures relatively lit- examples of what may occur are summarized in Table 2. tle is known with respect to the diff e rential pharm a c o d y- As a result of the pharmacodynamic and pharm a c o k i - namic, toxicologic, or pharmacokinetic pro p e r ties of the netic complexities associated with the use of racemic mix- individual enantiomers. Interactions between the enan- t u r es, together with adverse reaction and drug safety tiomers present in a racemic mixture may also occur such i s s u e s , 4 8 d rug stere o c h e m i s t ry became the subject of consid- that the observed pro p e rties of the racemate is not simply erable discussion. Initially, the debate was mainly within the product of the effects of the individual enantiomers. Such interactions may have a pharmacokinetic, pharm a- TABLE 2. EXAMPLES OF THE SIGNIFICANCE OF codynamic, or physiological basis. STEREOCHEMICAL CONSIDERATIONS IN Following administration of the individual enantiomers of DRUG DISPOSITION AND ACTION the antiarrhythmic agent disopyramide, no diff e rences are o b s e rved between the two stereoisomers in their pharm a c o- 1. Route of Administration kinetic pro p e rties (volume of distribution, clearance, or Verapamil: Observed concentration-effect relationship based 4 3 on total drug plasma level indicates a reduced effect following renal clearance). H o w e v e r, following administration of the oral compared to intravenous administration. Associated with racemate, the S-enantiomer shows a decreased plasma and s t e r eoselective first-pass metabolism of the more active S- renal clearance, lower volume of distribution, and incre a s e d enantiomer.49 half-life in comparison to (R)-disopyramide. These diff e r- 2. Formulation ences arise due to enantiomer-enantiomer interactions in Verapamil: Ratio R / S of Cm a x and AUC is significantly gre a t e r plasma protein binding which is concentration-dependent.4 3 following SR than IR formulations (Cm a x , SR, 5·83; IR, 4·52; Examination of the pharmacodynamic activity of the AUC, SR, 7·75; IR, 5·04). Variation thought to be due to con- centration and/or input rate related saturable first pass metabo- phenylpiperidine opioid analgesic picenadol indicates that lism of (S)-verapamil.50 the racemic mixture is a partial agonist at µ- r e c e p t o r s . 3. Drug Interactions Evaluation of the pro p e rties of the individual enantiomers Wa r farin: Most extensively examined drug with respect to reveals that the analgesic activity resides in (+)-(3S, 4R) - s t e reo selectivity in drug interactions, some agents selective for picenadol, whereas the (-)-3R, 4S-enantiomer acts as an the more active S- e n a n t i o m e r, (eg, phenylbutazone); others antagonist at the same re c e p t o r. Thus, the partial agonist selective for (R) - w a r farin (eg, cimetidine), others show no 51 activity of the racemate arises due to the greater potency of selectivity (eg, amiodarone). the agonist (+)-enantiomer compared to the weaker antago- 4. Aging 3 1 , 4 4 Hexobarbital: Stereoselective decrease in clearance with age. nist activity of (-)-picenadol. S-enantiomer 2-fold greater clearance in young compared to Indacrinone is a loop diuretic with uricosuric activity elderly; R-enantiomer, no age effect.52 evaluated for the treatment of hypertension and conges- 5. Disease tive heart failure. Following administration of the race- I b u p rof en: Plasma concentrations of (S) - i b u p r ofen lower than mate to man, serum uric acid levels incre a s e . 4 5 those of the R-enantiomer in cirrhotic patients; ratio of are a Examination of the pro p e r ties of the individual enan- under the plasma concentration time curve (S / R) 0·94 in cir- 53 tiomers indicates that the natriuretic activity resides in rhotic patients compared to 1·3 in healthy volunteers. the R- e n a n t i o m e r, whereas the uricosuric effects are pri- 6. Gender Mephobarbital: Oral clearance of R-enantiomer significantly marily associated with (S)-indacrinone but, following g reater in young men compared to young or elderly women, or administration of the racemate, the half-life of the S- e n a n- elderly men; S- e n a n t i o m e r, no significant diff e rences between tiomer is too short to prevent the increase in uric acid.4 6 groups.54 Manipulation of the enantiomeric composition from the l:l 7. Pharmacogenetics p ro p o rtion present in the racemate, by increasing the pro p o r- M e t o p r olol: Enantiomeric ratio (S / R ) of the area under the tion of the S- e n a n t i o m e r, resulted in preparations which were plasma concentration versus time curve decreases from 1·37 in extensive metabolizers to 0·90 in poor metabolizers of debriso- either isouricemic (S : R:4:1) or hypouricemic (S : R: 8 : 1 ) . 4 7 T h e 4 8 quine; the “total” plasma concentration effect re l a t i o n s h i p development of indacrinone was stopped in the mid-1980s shifts to the right in poor compared to extensive metabolizers.55 but, from the investigations carried out, the principle of 8. Race manipulation of the stereoisomer ratio to produce a pre p a r a- P r opranolol: Oral clearance of both enantiomers greater in tion with an improved therapeutic profile was established. black compared to white subjects; stereoselective for the R- In addition to interactions between stereoisomers, exam- enantiomer.56 ples may also be cited where stereochemical considerations Cm a x =maximum plasma concentration; AUC=area under the plasma con- have provided explanations of anomalies in the pharm a c o- centration versus time curve; SR=sustained release; IR=immediate release. logical profiles of drugs administered as racemates. Also, Hutt AJ. C N S S p e c t r u m s . Vol 7, No 4 (suppl 1). 2002.

M e d Works Media 18 April 2002 Academic Supplement the academic environment with the advocates of single tiomers present in a mixture, the supposed advantages of s t e reoisomers using such phrases as “isomeric ballast” and the single isomer product have not been realized. Sotalol “compounds containing 50% impurity” and maintaining is a nonselective β-blocking agent with class III antiar- that the use of racemates is “polypharm a c y,” with the pro- rhythmic activity; used as the racemate, the β- b l o c k i n g p o rtions in the mixture being determined by chemical pro p- activity resides in the (-)-enantiomer whereas both enan- e rties rather than therapeutic need. tiomers are equipotent with respect to their antiarrh y t h- A number of potential advantages may be associated with mic activity. 6 7 , 6 8 (+)-Sotalol there f o r e provides an the use of single stereoisomer products including: a n t i a rrhythmic agent without β-blockade, and the single • A less complex and more selective isomer was evaluated in patients with depressed ventricu- p h a rmacological pro f i l e lar function following myocardial infarction in the • Potential for an improved therapeutic index S u r vival With Oral d-Sotalol (SWORD) trial. The study • A less complex pharmacokinetic pro f i l e was terminated pre m a t u rely following re c ruitment of just • Reduced potential for complex drug interactions under 50% of the planned 6,400 patients due to • Less complicated relationship between plasma i n c r eased mortality in the treatment compared with the concentration and eff e c t placebo gro u p . 6 9 It has been proposed that the SWORD A compound frequently cited in articles advocating the findings are more a result of the therapeutic appro a c h use of single stereoisomers rather than racemic mixtures is than the value of the single enantiomer sotalol,7 0 and that the hypnotic teratogen thalidomide. The arguments are fre- the β-blocking and class III activity present in the race- quently presented in emotive terms presenting the case as a mate provides a more effective combination than antiar- situation where the use of a single isomer would have pre- rhythmic activity alone. Indeed, Shah and colleagues4 8 vented a tragedy. This view results from a publication in the have suggested that sotalol may provide an example of an late 1970s, which indicated that following administration of agent where a non-racemic mixture of enantiomers could the individual enantiomers to mice (SWS strain), both enan- be developed to provide an improved balance between the tiomers were sedatives whereas only (S)-thalidomide was two activities. t e r a t o g e n i c . 5 7 Rodents are, in fact, a poor model for thalido- mide teratogenicity and earlier studies in a more sensitive REGULATION AND CHIRAL DRUGS test species, New Zealand white rabbits, indicated that both Advances in stereochemical methodology for both the enantiomers, and the racemate, are teratogenic.5 8 , 5 9 An addi- synthesis and analysis of chiral drug molecules, together tional problem also arises due to the lack of stere o c h e m i c a l with an appreciation of the potential significance of stere o- stability of the individual enantiomers both in vivo and in chemical considerations in pharmacological and clinical v i t ro . 6 0 - 6 3 Thus, even if a single stereoisomer preparation of investigations, resulted in a change in philosophy with thalidomide had been available in the 1960s, patients respect to chiral pharmaceuticals. As a result of the incre a s- would still have been exposed to both enantiomers due to ing concern, drug stere o c h e m i s t ry became an issue for both the facile racemization of the material. Thalidomide is the pharmaceutical industry and the re g u l a t o r y authori- t h e re f o re a particularly poor example to be cited in support t i e s , 7 1 - 7 4 and a number of meetings were held in the late of arguments for single-isomer products. 1980s and early 1990s with the specific objective of dis- Examples may also be cited where a single stere o i s o m e r cussing the new technologies and the significance of chiral- is available and its enantiomer may have a therapeutic ity in pharmacology and therapeutics.7 5 - 7 7 advantage. The β- b l o c k e r, (S)-timolol, is currently available In 1992, the Drug Information Association (DIA) held a for both oral and topical use for the treatment of card i o v a s- workshop in Paris, entitled “Chirality at the Cro s s roads,” at cular disease and glaucoma. Following local administration which re p resentatives from the pharmaceutical industry and to the eye, systemic absorption of the drug takes place, and re g u l a t o r y authorities in the European Union, Nort h c a r diovascular and pulmonary effects have been America, Australia, and Japan discussed stere o c h e m i c a l re p o rt e d . 6 4 , 6 5 (R) - Timolol is between 50- to 90-fold, depend- issues relating to quality, safety, and eff i c a c y.7 7 The same ing on the test system used, less potent than the S- e n a n- y e a r, the Food and Drug Administration (FDA) published a tiomer in terms of β-blockade but only approximately 3-fold policy statement for the development of new stere o i s o m e r i c less potent in reducing intraocular pre s s u re .4 5 (S)- and (R) - d ru g s , 7 8 which was followed shortly afterw a rd by Euro p e a n timolol also appear to have opposite effects on retinal and guidelines in 1993.7 9 c h o roidal blood flow, with the R-enantiomer having the ben- The DIA workshop advocated a pragmatic approach to eficial effect of increasing flow.66 These data suggest that chiral drug regulation in that the decision re g a r ding the both enantiomers of timolol could be marketed with their s t e r eochemical form to be developed (single isomer or own specific therapeutic indications, the use of the R- e n a n- racemate) should be left to the applicant and based on tiomer for the treatment of glaucoma having the advantage q u a l i t y, safety, eff i c a c y, and risk-benefit ratio on a case- of reduced systemic eff e c t s . by-case basis.7 7 The published re g u l a t o r y guidelines T h e re have been instances where, following evaluation have essentially adopted the DIA approach and at pre s- of the pharmacological pro p e rties of the individual enan- ent there is no absolute re q u i r ement from any of the

April 2002 19 M e d Works Media Academic Supplement major agencies for the development of single enantiomer i n t e rconversion of stereoisomers should be evaluated, par- d r ugs. However, the choice of stereoisomeric form ticularly as this will aid in the decision making process to re q u i res scientific justification. develop either a single stereoisomer or a racemic mixture . 8 0 A number of arguments may be used to support the sub- As a result of the re g u l a t o r y attitudes, together with mission of a racemate including: advances in appropriate synthetic and analytical technol- • The individual stereoisomers are stere o c h e m i c a l l y o g y, the number of single-isomer NCEs submitted for unstable and readily racemize in vitro and/or in vivo a p p rov al to various re g u l a t o ry bodies since the early 1990s • P reparation of a single stereoisomer on a commerc i a l appears to have incre a s e d . 8 0 , 8 2 , 8 3 The figures derived fro m scale is not technically feasible such surveys need to be interpreted with some care, as the • The individual stereoisomers have similar pharm a c o- classification of compounds into the various categories orig- logical and toxicological pro f i l e s inally developed by Ariëns and colleagues8 depends to an • One stereoisomer is inactive and can be shown not to extent on the surv e y o r. However, the most recent available p r ovide an additional body burden or influence the f i g u res, arising from an examination of NCEs submitted to p h a rmacokinetic pro p e rties of the other the UK Medicines Control Agency between 1996 and 1999, • The use of the racemic mixture produces a superior indicate that the pro p o r tion of single-isomer synthetic therapeutic effect compared to either of the individual agents has increased, the number of chiral synthetic dru g s e n a n t i o m e r s being approximately 47% of the total, of which 65% were • The therapeutic significance of the compound in re l a t i o n single stereoisomers (Figure 4).8 0 While the number of to the disease state and adverse drug reaction pro f i l e agents is considerably smaller than that used in the original T h e re is considerable agreement with respect to the re g- s u rv e y,8 the trends are evident. u l a t o ry re q u i rements for the development of chiral drugs in E u rope, Japan, and the US, the main diff e rences arising RACEMIC OR CHIRAL SWITCH f rom the general approach to re g u l a t o ry matters in these In addition to new drug development, a number of estab- t h ree are a s . 8 0 , 8 1 lished agents, marketed as racemates, have been re - e v a l u a t e d Within the European Union, stereochemical considera- as single stereoisomer pro d u c t s . 8 4 These so-called racemic or tions start with the chemical development process, proof of chiral switches have resulted in a number of compounds s t ru c t u re, and stereochemical configuration being re q u i re d . being re-marketed as single stereoisomers in several coun- The final product must be characterized, as for any dru g , tries (Table 3). However, the development of single stere o i s o- with the additional re q u i rem ent to establish the stere o c h e m- mers from previously marketed racemic mixtures is not a ical purity of the material. With single stereoisomer pro d- trivial matter. In two cases [dilevalol, the β-blocking, ucts, the unre q u i red stereoisomer(s) arising either during R , R- s t e reo isomer of the combined α- and β-blocking dru g m a n u f a c t u re and/or storage are re g a rded as impurities and labetalol, and (R)-fluoxetine], development has been stopped t h e re is an additional re q u i rement to show that unaccept- due to unexpected adverse eff e c t s . 4 8 , 8 5 , 8 6 able changes in stereochemical composition do not occur. In W h e r e a single stereoisomer is developed from an addition, the use and stereochemical purity of individual a p p rov ed racemate the re g u l a t o ry agencies allow the use of batches of material must be known so that they may be bridging studies between the original and the new submis- related to safety and clinical investigations.8 0 sion. Obviously, potential difficulties may arise if the spon- P r eclinical and clinical investigations on single sor of the single stereoisomer was not responsible for the s t e reoisomer products are carried out as for any other new original development of the dru g . 8 0 In cases of the chiral chemical entity (NCE), with the additional re q u i reme nt to examine the stereochemical stability of the material in vivo (ie, does inversion of configuration, either biochemically or chemically mediated, take place in vivo?). In such instances, the stereoisomer formed is treated as a metabo- lite. Preclinical evaluation of a racemic drug should include p h a rmacodynamic, pharmacokinetic, and appropriate toxi- cological investigation on both enantiomers and the race- mate. In some instances, clinical investigations on the thre e f o rms of the drug may also be re q u i re d . The FDA guidelines are similar in many respects to those in Europe in that development of racemic mixture s may be appropriate. The manufacture of a product should FIGURE 4. SURVEY OF THE STEREOCHEMISTRY OF be controlled to ensure its stereochemical composition, and NEW CHEMICAL ENTITIES ASSESSED BY THE MEDICINES CONTROL AGENCY the composition of the materials used in pharm a c o l o g i c a l , BETWEEN 1996 AND 199980 toxicological, and clinical studies must be known. Hutt AJ. C N S S p e c t r u m s . Vol 7, No 4 (suppl 1). 2002. S i m i l a r l y, in pharmacokinetic investigations, the possible

M e d Works Media 20 April 2002 Academic Supplement switch the pharmacokinetic profile of the selected stere o i s o- sion, but if such dimensional considerations result in mer should be compared, following administration as such i m p roved drug safety and efficacy then the double-tro u b l e and as a component of the racemate, to ensure that interac- involved will have been worthwhile. C N S tions between the two enantiomers do not occur. The examples cited in Table 3 are those that have REFERENCES u n d e r gone a successful chiral switch, or have been with- 1 . C o r n f o rth JW. In: Eggerer H, Huber R, eds. S t ru c t u re and Functional Aspects drawn or had development stopped due to adverse of Enzyme Catalysis 32 Colloquium-Mosbach. Berlin, Germany: Springer- 8 4 - 8 6 Verlag; 1981:3. e ff e c t s . H o w e v e r, there are a number of agents at vari- 2 . Mason S. The left hand of nature. 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Penicillamine, a new oral therapy for Wi l s o n ’s Disease. Am J Med. NSAID Austria, Switzerland 1 9 5 6 ; 2 1 : 4 8 7 - 4 9 5 . Dexketoprofen NSAID Spain, UK 24. Tu J-B, Blackwell RQ, Lee PF. D, L-Penicillamine as a cause of optic axial neuri- Levobupivacaine Local anaesthetic UK tis. J A M A . 1 9 6 3 ; 1 8 5 : 8 3 - 8 6 . 25. Walshe JM. Chirality of penicillamine. Lancet. 1 9 9 2 ; 3 3 9 : 2 5 4 . (S)-Ketamine Anaesthetic Germany 26. Lee A, Lawton NF. Penicillamine treatment of Wi l s o n ’s disease and optic neuro p a- Esomeprazole Proton-pump UK, US t h y. J Neurol Neuro s u rg Psych. 1 9 9 1 ; 5 8 : 7 4 6 . inhibitor 27. Crossley R. Chirality and the Biological Activity of Dru g s . Boca Raton, Fla: CRC (R)-Salbutamol β2-agonist US P ress; 1995. (R)-Fluoxetine Antidepressant Development stopped 28. Hutt AJ. Drug chirality and its pharmacological consequences. In: Smith HJ, ed. 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