Academic Supplement Single-Isomer Science: The Phenomenon and Its Te rm i n o l o g y By Joseph Gal, PhD

ABSTRACT For more detailed information, the reader is re f e rred to text- Single-isomer drugs are of great importance in modern books of basic organic chemistry; advanced treatments of therapeutics. In this article, the basics of the underlying the subject are also available, including an excellent mono- phenomenon are explained. Some molecules are chiral, ie, g r a p h 3 and a highly informative and entertaining volume on their mirror image is not superposable on the original. The a broad variety of aspects of the phenomenon.4 most common element producing molecular chirality is a chiral center, typically a carbon atom carrying four diff e r- MIRROR, MIRROR ON THE WALL... ent groups. The mirro r-image molecules are termed e n a n- C e rtain objects have the pro p e rty that their mirror image t i o m e r s , but the less specific terms s t e r e o i s o m e r s a n d is not entirely identical with the original. The most familiar isomers are also used. A substance consisting of only one of tools for the illustration of this phenomenon are the two the two enantiomers is a single enantiomer or single iso- human hands. If one holds, say, the left hand in front of a m e r, and the 1:1 mixture of the enantiomers is the racemic m i rro r, one finds that the image in the mirror is that of the m i x t u re or racemate. A graphical convention that conveys right hand. Clearly, the right hand is the mirror image of the the three-dimensional aspects of chiral molecules drawn in left hand, and vice versa. Furt h e rm o re, while the two hands two dimensions, as well as two nongraphical conventions, of an individual are identical in appearance, one cannot based on optical rotation and configuration, are used to “ m e r ge” perfectly the left hand into the right one (or the identify enantiomers. Optical rotation is a physical pro p- right hand into the left). This is in contrast to the mirro r e r ty of single enantiomers and involves rotation of the image of another kind of object, eg, the cue ball used in bil- plane of plane-polarized light, each pure enantiomer rotat- l i a r ds. The mirro r-image of the ball is identical in all ing with equal magnitude but in the opposite dire c t i o n respects to the original and is indistinguishable from it. (dextro and levo). Configuration is the actual arrangement F u rt h e rm o re, the mirror image of the ball can be fully and in space of the atoms of chiral molecules. Two systems of p e rfectly “merged” into the original. Thus, the mirror image indicating configuration are in use. One employs D and L of the ball is superposable on the original, while the mirro r to denote the respective enantiomers, and is applicable only image of a hand is not superposable on its original. to α-amino acids and carbohydrates. The other is a univer- An object whose mirror image is not superposable on the sal system using R and S as descriptors for the two possible original is termed c h i r a l (ch p ronounced as k and the word a r rangements, re s p e c t i v e l y, of the atoms around the chiral rhymes with viral), and the phenomenon is called c h i r a l i t y, c e n t e r. Interest in chiral drugs stems from the fre q u e n t l y f rom χειρ (cheir), the Greek word for the hand. H a n d e d n e s s o b s e r ved biological diff e r ences between enantiomers. Such is also a useful term to refer to the phenomenon of chirality. enantioselectivity is the result of diff e rent interactions of Chiral objects abound in nature—indeed, the presence of the drug enantiomers with target receptors that are them- chirality ranges from the subatomic to the macro s c o p i c selves chiral and single-enantiomeric. w o r l d . 4 , 5 M a c r oscopic chiral objects include, for example, C N S S p e c t ru m s . 2002;7(suppl 1):8-13 anatomical parts—eg, the hands, feet, and ears—and some c o rresponding clothing items—eg, gloves and shoes— are INTRODUCTION also chiral. Helical or spiral stru c t u res also have handed- Single-isomer drugs have assumed a great deal of impor- ness, eg, screws are chiral, one form having a left-handed tance in recent years, and are poised to become even more t h read and its mirror image a right-handed thread. Helical significant in the future . 1 , 2 The foundation of single-isomer sea shells, similarly, have right-handed or left-handed helic- d rugs is a chemical phenomenon involving the thre e - d i m e n- ity and are chiral; in arc h i t e c t u r e, columns with a spiral sional aspects of molecules (stere o c h e m i s t ry), and a thor- design have handedness (Figure 1).6 The umbilical cord is ough appreciation of the basic and clinical sciences of chiral by virtue of its helical vasculature, and it has been single-isomer drugs is not possible without an understand- shown that left-handed helices predominate in at least one ing of the pertinent fundamentals and terminology of the n e w b o rn population.7 phenomenon. The purpose of this article, there f o re, is to H o w e v e r, our concern here is with molecules and dru g s , p rovide a description of the basic relevant concepts and lan- and we must there f o re turn our attention from the world of guage. Naturally, the discussion will be limited in scope and m a c r oscopic chiral objects to the world of molecules and will be aimed at the non-expert in organic stere o c h e m i s t ry. chemical compounds. Interest in chiral drugs stems fro m

D r. Gal is professor of medicine, pharm a c o l o g y, and pathology in the Division of Clinical Pharmacology at the University of Colorado School of Medicine in Denver. M e d Works Media 8 April 2002 Academic Supplement the fact that the two mirro r-image forms of such substances merism exist, with chirality being the basis of one type. often differ significantly, even drastically, in their biological Thus, the two mirro r-image chiral molecules can be e ffects (see below). termed stereoisomers, but this term is general and not spe- cific to chirality. The precise term for the two mirro r- MOLECULAR HANDEDNESS image stereoisomers is e n a n t i o m e r ( f r om the Gre e k Some molecules are chiral by virtue of the presence of a enantios, opposite), and should be used for rigorous accu- c h e m i c a l - s t ructural element that produces chirality. The most r a c y. However, stereoisomer is often used in the chirality common structural chiral element producing chirality is a context to refer to enantiomers. Furt h e rm o re, in the phar- carbon atom with a specific pattern of groups connected to it maceutical and pharmacological context, enantiomer is (substitution pattern). When a carbon atom has four diff e re n t often replaced with isomer, an even less specific term chemical groups (substituents) bonded to it, the geometric than stereoisomer but one which has nevertheless come shape of the bonding arrangement is in the form of a tetrahe- into use in re f e rence to the enantiomers of chiral dru g s d ron. For example, in the molecule shown in Figure 2, the because of its more familiar nature and short form. carbon atom carries four substituents––hydrogen (H), fluorine Overall, then, a compound that is made up of only one of (F), chlorine (Cl), and bromine (Br)––and the four bonds point the two possible mirro r-image molecules is often re f e rred to t o w a rd the four corners of a tetrahedron. Such a carbon atom as a single enantiomer, single stere o i s o m e r, or, again, some- in a molecule is called a chiral center, and the molecule in what loosely, as a single isomer. When the chemist synthe- F i g u re 2 is chiral, ie, it can exist in two forms that are non- sizes compounds made up of chiral molecules using superposable on each other and are related as an object and o rd i n a ry chemical reactions, the product obtained is usually its mirror image. An overwhelming majority of chiral mole- the 1:1 mixture of the two enantiomers, called the r a c e m i c cules owe their chirality to the presence of a carbon chiral m i x t u re o r, simply, the r a c e m a t e. To obtain the single enan- c e n t e r, but atoms other than carbon, eg, phosphorus and sul- t i o m e r, one of a variety of enantiospecific chemical tech- f u r, can, when appropriately substituted, also function as chi- niques must be employed. Such methods are highly ral centers. Furt h e rm o r e, certain structural elements other sophisticated today, and the preparation of virtually any sin- than a chiral center atom can also give rise to chirality. gle-enantiomer drug is possible in the laboratory or on a The two mirro r-image forms of a chiral molecule are manufacturing scale. Substances of chiral molecules pro- s t e r eoisomers. Two molecules are stereoisomers if they duced by nature, on the other hand, usually occur in single- have the same basic framework and sequence of bonding enantiomeric form. of the atoms but differ in the three-dimensional arr a n g e- If a molecule has more than one chiral center, the situa- ment of (some of) the atoms. Several types of stere o i s o - tion becomes a little more complex from the chirality stand- point. Thus, as discussed above, if there is only one chiral c e n t e r, two stereoisomers (ie, two enantiomers) are possible. If, however, the number of chiral centers, n, in the molecule is greater than 1, the total number of stereoisomers possible is 2n. For example, if there are three chiral centers in the molecule, eight stereoisomers are possible, which can form

FIGURE 1. L E F T-HANDED- AND RIGHT- H A N D E D - SPIRAL CHIRAL COLUMNS FROM THE C O U RT OF THE 13TH CENTURY CLOISTER ADJACENT TO THE CHURCH OF ST. PA U L - O U T S I D E - T H E - WALLS IN ROME Reproduced with permission from Taylor & Francis Ltd. from: Schurig V. FIGURE 2. A CHIRAL MOLECULE CONTAINING A E n a n t i o m e r. 1 9 9 6 ; 1 : 1 4 7 - 1 4 9 .6 TETRAHEDRAL CARBON CHIRAL CENTER Gal J. C N S S p e c t r u m s. Vol 7, No 4 (suppl 1). 2002. Gal J. C N S S p e c t r u m s. Vol 7, No 4 (suppl 1). 2002.

April 2002 9 M e d Works Media Academic Supplement four distinct racemates, ie, four sets of enantiomers (mirro r- s i ngl e isomers. Two such methods are in use, one involving image stere o i s o m e r s ) . optical rotation and another addressing configuration.

A PICTURE WORTH A THOUSAND WORDS: Optical Rotation GRAPHICAL REPRESENTATION Optical rotation is a physical pro p e r ty of substances OF CHIRAL MOLECULES made up of chiral molecules. To observe and measure opti- When the stru c t u re of a chiral molecule is drawn on cal rotation we must use plane-polarized light. In such light paper or shown on a projection screen (in two dimensions), a the electromagnetic radiation is polarized in a single plane. specific convention is used to convey the thre e - d i m e n s i o n a l When such light travels through a sample of a substance aspects. For example, for the chiral amino acid alanine, the made up of chiral molecules, the plane of polarization of the convention is shown in Figure 3. As seen in the figure, the light emerging from the sample is rotated with respect to the chiral carbon center that carries the four diff e r ent sub- original plane. The extent of rotation is the angle between stituents is considered to be centered in the plane of the the original plane and the rotated plane. Furt h e rm o re, the illustration (paper or projection screen). Now, to depict the amount of rotation is a function of the identity of the sub- t h r ee-dimensional (tetrahedral) arrangement of the four stance and the conditions of measurement, eg, the solvent g roups around the chiral carbon center, the four bonds are used, pH, the temperature, the wavelength of light used, the depicted as three diff e r ent types. Two of the bonds are concentration of the substance (if it is in solution), and the drawn as simple straight lines and are considered to be length of the sample container. located in the plane of the illustration (in Figure 3 these two When the plane-polarized light is viewed as it emerg e s bonds are those linking the amino group, NH2, and the car- after traveling through the substance, the rotation with boxy group, COOH, to the chiral center). respect to the original plane may be in either the clockwise The third bond is drawn as a solid dark wedge with its or the counterclockwise direction. A substance that causes thin end at the chiral carbon and the thick end at the sub- clockwise rotation is termed d e x t r o ro t a t o r y and one that stituent (the methyl group, CH3, in our example in Figure causes counterclockwise rotation is l e v o ro t a t o ry. The dire c- 3). The bond thus originates in the plane of the paper but tion of rotation is also often indicated with the (+) and (-) s i g n s , gradually leaves the plane and points toward the viewer. the former meaning dextro rotation and the latter levoro t a- F i n a l l y, the fourth bond is drawn as a broken wedge consist- tion. In addition, one finds in the literature the frequent use ing of parallel lines. This bond, too, originates at the chiral of the lower-case letters d and l to indicate dextro and levo, center in the plane but leaves the plane and points behind re s p e c t i v e l y. This usage is, however, strongly discouraged the paper, ie, away from the viewer (in Figure 3 it is the because the lower-case letters are often confused with the bond linking the carbon to the hydrogen atom, H). u p p e r-case D and L, which have nothing to do with ro t a t i o n but instead refer to configuration (see below). IDENTIFICATION SYSTEMS The magnitude (angle) of rotation is expressed in FOR SINGLE ISOMERS d e g rees, and when the optical rotation is measured under a Using the above convention, then, a reasonable two- defined set of standard conditions the rotation is term e d dimensional illustration of the three-dimensional aspects of specific rotation. The specific rotation is equal in magnitude chiral molecules can be provided. There is still, however, a and opposite in direction (dextro versus levo) for the two need for non-graphical, ie, textual, means of identifying enantiomers. Thus, the sign and value of the specific ro t a- tion is a useful means of rigorously identifying the enan- tiomers. In addition, simply stating the direction of ro t a t i o n caused by a given enantiomer (see below) is also useful as an identification of the single isomer.

Configuration Configuration means the actual arrangement in space of the substituents around the chiral center. Thus, there are two possibilities––two configurations—for each chiral cen- t e r, corresponding to the two mirro r-image forms. The two f o rms can be readily drawn on paper using the convention described above, but there is also a need for a system for the FIGURE 3. THE CONVENTION FOR THE convenient identification and description of the configura- R E P R E S E N TATION OF THE THREE- tion of the mirro r-image molecules. In fact, two such sys- DIMENSIONAL ASPECTS OF A CHIRAL MOLECULE IN TWO DIMENSIONS tems are in use: the D/L system and the R / S s y s t e m . Note that the carbon atom at the chiral center is not explicitly drawn. The D/L System. A previously widely used system, it is Gal J. C N S S p e c t r u m s. Vol 7, No 4 (suppl 1). 2002. now applied only to α-amino acids and sugars. The sys- tem arbitrarily assigns the D and L indicators to the two

M e d Works Media 10 April 2002 Academic Supplement enantiomers according to a convention, as shown in Figure c e n t e r, since the atomic number of carbon is 6. Finally, the 4 for the amino acid alanine. The side chain in alanine is lowest priority, 4, goes to the hydrogen atom, its atomic a methyl (CH3) group; in the other chiral α-amino acids number being 1. the side chains differ but the configurations of the D- and L- (2) View the molecule with the lowest-priority substituent enantiomers remain as shown in Figure 4. The use of the f a rthest away. This is shown in Figure 5, since the hydro g e n D/L system for carbohydrates is more complex because of atom (priority 4) is behind the plane of the page, ie, it is the the presence of more than one chiral center in the mole- substituent farthest from the viewer. cules. It is important to remember that D and L refer to con- (3) Starting at the highest-priority group (priority 1) draw figuration and not to optical rotation, despite the temptation a circle around the molecule while following the descending to interpret D as dextro and L as levo. priority ord e r, ie, going past priority 2 and on to priority 3 The R / S System. This system was introduced beginning (the substituent of priority 4 is not included in this opera- in the early 1950s and has become the most widely used tion). If the motion to draw the circle is clockwise the con- method of specifying configuration, except for amino acids figuration is R, and if it is counterclockwise it is S. For the and sugars, as described above. The R / S system is univer- molecule in Figure 5, the circle is drawn clockwise and sally applicable to molecules containing chiral centers and t h e re f o re the configuration is R, as shown. has brought order into the field of identifying enantiomers. Several additional rules are used by the R / S system to Indeed, its leading developer, the late V. Prelog, was allow the assignment of priority order in virtually any chiral a w a rded the 1975 Nobel Prize in chemistry, in part for his molecule. Also, it is clear that if the molecule has more than work on the R / S s y s t e m . 8 one chiral center, the configuration of each of them must be The R/S system assigns the descriptors R and S to the given (with an R or an S) for the full specification of the con- two forms, re s p e c t i v e l y, of a chiral center, depending on figuration of the molecule. the spatial arrangement of the substituents. The two let- ters are derived from the Latin words re c t u s and s i n i s t e r RELATIONSHIPS BETWEEN THE VARIOUS for right and left, re s p e c t i v e l y. The assignment of the SYSTEMS OF IDENTIFYING ENANTIOMERS descriptor to a given arrangement (configuration) at the Considering the above systems for the identification and chiral center is made on the basis of arbitrary but re l a- specification of chiral molecules and their substances, one tively simple rules. An example is given in Figure 5. The might ask the question, first, whether there is a corre l a t i o n p rocess of determining the correct descriptor for a chiral between optical rotation and configurational descriptor when center is as follows: comparing diff e rent molecules. The answer is that there is no (1) Assign a priority order to the four substituents at the d i rect relationship between the sign of rotation [(+) or (-), ie, chiral center on the basis of the atomic numbers (from the d e x t ro or levo] and the configurational indicators R, S, L, and Periodic Table of the elements) of the atoms directly con- D. For example, L-alanine is levoro t a t o ry, while L-valine is nected to the chiral carbon center. In the example shown in F i g u re 5 the fluorine atom (F) receives priority 1 (highest) since its atomic number is 9; priority 2 goes to the CH3- O - g roup because the atomic number of its oxygen atom, linked to the chiral center, is the second highest, with the value of 8; priority 3 goes to the methyl group bonded to the chiral

FIGURE 5. THE METHOD OF ASSIGNING THE C O N F I G U R ATIONAL DESCRIPTORS IN THE R/S S Y S T E M FIGURE 4. THE D/L SYSTEM OF CONFIGURA- The priority numbers are shown (see text for details). TIONAL NOTATION AS APPLIED TO THE F=atomic number: 9; O=atomic number: 8; C=atomic number: 6; and ENANTIOMERS OF THE AMINO ACID H=atomic number: 1. Numbers in parenthesis indicate priority order A L A N I N E ( 1 = h i g h e s t ) . Gal J. C N S S p e c t r u m s. Vol 7, No 4 (suppl 1). 2002. Gal J. C N S S p e c t r u m s. Vol 7, No 4 (suppl 1). 2002.

April 2002 11 M e d Works Media Academic Supplement d e x t ro ro t a t o ry. Also, (S)-amphetamine is dextro ro t a t o ry while d i r ection of optical rotation (ie, dextro or levo) is actually (S) - p ropranolol is levoro t a t o ry. To further complicate matters, o fficially an integral part of the nonpro p r i e t a ry name. in some cases the sign of rotation of a substance can change In those cases, however, where the name does not depending on the conditions of measurement. For example, include dextro or levo, it may still be necessary in cert a i n the single-isomer antibacterial drug chloramphenicol is dex- situations to express the single-isomer nature of the agent, t ro ro t a t o ry when dissolved in ethanol but levoro t a t o ry in ethyl eg, to refer to a single-isomer version of a racemic drug or to acetate, while its configuration, obviously, does not change. emphasize that the name in fact refers to a single-isomer Overall, it is useful to keep in mind that optical rotation is a agent. In such cases dextro or levo can be added as a pre f i x physical pro p e rty of bulk substance while configuration is the b e f o r e the non-pro p r i e t a ry name, eg, d e x t ro-fluoxetine or actual arrangement in space of the atoms of chiral molecules. l e v o-morphine. It is important to re m e m b e r, however, that Another relevant question in this context is whether there the prefix here is not officially part of the nonpro p r i e t a ry is a direct relationship between the two systems of configu- name. It is also seen that the prefix is italicized and sepa- rational notation (D/L and R / S). Here too, the answer is that rated from the drug name with a hyphen, a format that t h e re is no relationship. In those cases where both systems clearly distinguishes these names from those that include a re applicable (eg, α-amino acids) a molecule that has the D the rotation information as an integral part of the name, as or L configuration may be R or S by the R/S n o m e n c l a t u re , discussed in the previous paragraph. depending on the nature of the substituents around the chi- Another method to indicate optical rotation and there b y ral center. For example, L-alanine is (S )- a l a n i n e but L-cys- single-isomer character via the drug name is to use (+) or (-) teine is (R)-cysteine. Thus, even though these two instead of the dextro or levo prefix, eg, (+)-fluoxetine or (-)- single-enantiomer amino acids have the same thre e - d i m e n- morphine. Here too, the sign of optical rotation is not off i- sional arrangement of the substituents at the chiral center cially part of the nonpro p r i e t a r y name but is used to and the same descriptor in the D/L system, their configura- indicate the single-isomer character of the drug and the tional descriptors in the R / S system diff e r. identity of the single enantiomer in question.

WHAT’S IN A NAME? DRUG NOMENCLATURE Configurational Descriptor in the Name FOR SINGLE ISOMERS The use of configurational descriptors in nonpro p r i e t a ry A p p roximately 50% of all drugs consist of chiral mol- names is less common and less convenient than using dextro ecules, and about one half of these are marketed as race- or levo. R and S a r e less familiar than dextro/levo, and mates and the other half as single isomers. Furt h e rm o re , another problem is that if the number of chiral centers in the as mentioned above, the importance of single-isomer molecule is greater than one, several Rs and/or Ss would have d r ugs is growing. It is clear, there f o re, that the naming of to be used in the name, an impractical re q u i rement. There single-isomer drugs is a significant issue. Drug names a re, however, several examples in which the configurational can be pro p r i e t a r y (“brand”), non-pro p r i e t a r y descriptor is incorporated into the nonpro p r i e t a ry name. (“generic”), or chemical names. We will not addre s s F u rt h e rm o re, as new single-isomer drugs are introduced, the chemical and pro p r i e t a ry names here. As for nonpro p r i- number of such names is likely to increase. Existing exam- e t a ry names, most single-enantiomer drug names do not ples include the new antidepressant drug escitalopram (S- indicate the fact that the drug is a single isomer. For citalopram), the gastrointestinal agent esomeprazole example, the name “morphine” does not express in an (S-omeprazole), esflurbiprofen (S- f l u r b i p rofen), arbutamine explicit manner that the drug is in fact a single isomer. In (R-butamine), etc. In these names the configurational some cases, however, the names do express explicitly the descriptor is fully integrated into the nonpro p r i e t a ry name. single-enantiomer character of the agent. It is also note- It is seen that for inclusion in drug names, the descrip- w o r thy that a proposal has been made to ro u t i n e l y tors S and R must be converted to a more convenient form , include information on the single-isomer nature and n a m e l y, “es” and “ar,” re s p e c t i v e l y. It is also notewort h y identity of drugs in the nonpro p r i e t a r y name.9 that in all of these examples there is only one chiral center in the molecule, allowing the use of one simple pre f i x . Optical Rotation in the Name Such incorporation of configurational descriptors is It is sufficient to consult practically any compre h e n s i v e undoubtedly a commendable approach to providing more d rug compendium to find that many single-isomer dru g s i n f o rmative nonpro p r i e t a ry drug names. Nevertheless, such have nonpro p r i e t a r y names that begin with “dextro” (or names do have some disadvantages. First, it is clearly unde- “dex”) or “levo” (or “lev”). Such names provide two pieces sirable to have a large number of drugs whose names begin of information: first, the fact that the drug is a single isomer, with the same two letters, a scenario which can lead to con- and, second, dextro or levo in the name gives the sign or fusion in drug names (the same objection can be made to d i rection of optical rotation, ie, the identity of the isomer. d e x t ro/levo and certain other drug names).1 0 Second, there Examples include dextroamphetamine, dextro m e t h o r p h a n , exist already many drugs whose names begin with “es” or dexmedetomidine, levodopa, levorphanol, etc. It is impor- “ar” without any connection to the configurational descrip- tant to recognize that in such cases the indicator of the tors. Examples include esculamine (non-chiral), esafloxacin

M e d Works Media 12 April 2002 Academic Supplement

(racemic), esmolol (racemic), esorubicine (five chiral cen- Let us assume that the two hands of one individual re p re- ters), arnolol (racemic), arteflene (four chiral centers), sent the two drug enantiomers, and the right hand of another arprinocid (non-chiral), and argimesna (S c o n f i g u r a t i o n ) . individual re p resents the biologic receptor mediating the Such names could be erroneously interpreted to indicate action of the drug. When these two individuals shake hands single-isomer character and/or an incorrect configuration if in the normal fashion, employing the respective right hands, the practice of using “es” and “ar” in the drug name to a comfortable interaction occurs. However, if the individual mean (S) or (R) became widespread. In fact, it has been sug- whose two hands re p r esent the two drug enantiomers gested that re g u l a t o ry authorities are likely to object to such attempted to use the left hand instead, the handshake n o m e n c l a t u re in the future . 1 0 between the left hand (“drug”) and the right hand (“re c e p- If the name does not incorporate the configuration, it can tor”) would not work well and would have an entirely diff e r- also be indicated by adding (S)- or (R)- as a prefix before the ent character from that of the normal (right hand-right hand) n o n p r o p r i e t a ry name, eg, (R)-fluoxetine or (S) - b u p ro p i o n . handshake. Clearly, then, the left and right hands of one H e re too (as for the separate dextro/levo prefixes above), the individual (“the two drug enantiomers”) differ in their abil- configurational descriptors are not officially part of the non- ity to interact with one hand of another individual (“the p ro p r i e t a ry name but are used to indicate explicitly the sin- receptor”). It is to be noted that such a fundamental diff e r- gle-isomer nature of the agent in question and its ence between the two handshakes occurs despite the com- configuration. The descriptor may be added to the nonpro- plete identity (except for mirro r-image character) of the left p r i e t a ry name of a racemic drug to refer to one of its enan- and right hands. The diff e rence in the two handshakes is tiomers, or to the name of a single-isomer agent in order to due entirely to the chiral nature of the three hands involved. specify its configuration. This is obviously a highly oversimplified model, and, nat- u r a l l y, the interactions of a drug with a biological re c e p t o r Optical Rotation and Configurational m a c r omolecule are a great deal more complex. Descriptor in the Name N e v e rtheless, our simple model does illustrate the underly- Often both the optical rotation and the configuration ing fundamental reason for diff e rences in the interactions of a re useful in discussing single-isomer drugs, and in such the two enantiomers of chiral drugs with their biological tar- cases both the configurational descriptor and the ro t a t i o n get molecules, namely, that two enantiomeric (mirro r- i m a g e ) indicator can be added to the nonpro p r i e t a r y name, eg, s t ru c t u res differ in principle in their ability to interact with (S)-(-)-bupivacaine, (R) - ( + ) - p r opranolol. It is not sug- another chiral stru c t u re. Furt h e rm o re, if the interactions do gested that such names become nonpro p r i e t a r y names, d i ffer the effects mediated by the receptor will be diff e re n t . but only that in some discussions of single-isomer dru g s , The result is of course potential enantiomeric diff e rences in the configurational and/or optical-rotation inform a t i o n p h a rm a c o l o g y, therapeutic effects, toxicity, metabolism, etc. may be useful or required. C l e a r l y, the two enantiomers of chiral pharm a c o l o g i c a l agents are, in many cases, diff e ren t drugs, and should be SINGLE ISOMERS, DRUG RECEPTORS, t r eated as such. Indeed, in 1992 the US Food and Dru g AND DRUG ACTION Administration issued new guidelines that govern the devel- As mentioned above, interest in the phenomenon of opment of new drugs from the chirality standpoint. While chiral drugs stems from the fact that the two enantiomers these guidelines do not ban the introduction of new racemic often differ in their biological effects. Indeed, it can be agents, they strongly favor the development of single-isomer safely said that for a given chiral drug the two enan- d r ugs. Similar regulations have been adopted by major tiomers will almost always differ significantly in some d ru g - re g u l a t o ry agencies around the world (in the Euro p e a n aspect of their pharmacological, pharmacokinetic, thera- Union, Japan, etc). We are there f o re at the threshold of a peutic, and/or toxic effects. Furt h e rm o re, such biological new era of single-isomer therapeutics. C N S enantioselectivity (ie, diff e r ences between the enan- tiomers) is often large. REFERENCES 1 . Eichelbaum M, Gross AS. Stereochemical aspects of drug action and disposition. Adv Drug Res. The reasons for enantiomeric diff e rences lie in the hand- 1 9 9 6 ; 2 8 : 1 - 6 4 . edness of nature itself: the biological target molecules (pro- 2 . Stinson SC. Chiral drugs. Chem Engin News. 2 0 0 0 ; 7 8 : 5 5 - 7 8 . 3 . Eliel EL, Wilen SH, Mander LN. S t e re o c h e m i s t ry of Organic Compounds. New York, NY: John Wiley & teins, nucleic acids, lipids, etc) that serve as mediators of Sons, Inc; 1994. d rug action, transport, or metabolism are themselves chiral 4 . G a r dner M. The New Ambidextrous Universe. 3 rd Revised Edition. New York, NY: W. H. Freeman and Company; 1990. and occur in single-isomeric form. The interactions of the 5 . H e g s t rom RA, Kondepudi DK. The handedness of the universe. Sci Am. 1 9 9 0 ; 2 6 2 : 1 0 8 - 1 1 5 . 6 . Schurig V. Homochiral vs. heterochiral pairs of double helices in art. E n a n t i o m e r. 19 96;1:147-149. two drug enantiomers with the single-isomer receptor are in 7 . Fletcher S. Chirality in the umbilical cord. Br J Obst Gyn. 1 9 9 3 ; 1 0 0 : 2 3 4 - 2 3 6 . principle diff e rent, and the result often is a significant dif- 8 . P relog V. Chirality in chemistry. S c i e n c e . 1 9 7 6 ; 1 9 3 : 1 7 - 2 4 . 9 . Simonyi M, Gal J, Testa B. Signs of the times: the need for a stereochemically informative generic name f e r ence between the drug enantiomers in their actions system. Trends Pharmacol Sci. 1 9 8 9 ; 1 0 : 3 4 9 - 3 5 4 . and/or disposition. Using the hands as models for the dru g 1 0 . Stinson SC. Counting on chiral drugs. Chem Engin News. 1 9 9 8 ; 7 6 : 8 3 - 1 0 4 . enantiomers and the biological drug re c e p t o r, we can illus- trate the conceptual basis of such enantiomeric diff e re n c e s in drug action.

April 2002 13 M e d Works Media 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 chiral drugs. 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 racemic mixture 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 opioids, 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 chirality 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 escitalopram, 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 analgesic 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 opiate 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 levomethorphan 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 dextropropoxyphene (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 (opioid analgesic) f int (+)-(3S,4R)–picenadol, µ–receptor agonist o rgan—hepatic metabolic clearance (CLH), renal clear- (-)-(3R,4S)–picenadol, µ–receptor antagonist 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)-ketamine 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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