Geometric isomerism and chirality: the USAN perspective
Geometric isomerism and chirality
Several decades ago, most pharmaceuticals with an asymmetric carbon (chiral center) were sold as mixtures of enantiomers. The introduction and widespread use of asymmetric synthesis and chiral separation technologies have made it possible for pharmaceutical manufacturers to develop single-enantiomer drugs. Another factor has been the publication of formal FDA guidelines, which encourage the development of chiral drugs.1 The market share of single-enantiomer drugs increased from 27percent in 1996 to 39 percent in 2002.2,3 The Business Communications Company projects that revenue from chiral drug development will continue to grow at an average annual rate of 10.2 percent annually, from 75.0 billion in 2003 to 122.0 billion in 2008.4 However, these projections, when based on past product introductions, may or may not reflect what is currently in the pipeline.
Before a drug reaches the NDA stage, companies must apply for a generic name through the US Adopted Names (USAN) program. The USAN Council assigns generic names to all drugs that have entered clinical trials and have some commercial potential. Drugs with proven benefit typically reach the market a few years after they receive a USAN. Thus, the substances to which USANs are assigned reflect the pharmaceutical pipeline in a given year. Examining the types of compounds that received USANs gives a good picture of the types of compounds that are undergoing clinical development and may become commercialized in a few years’ time.
This document explores the “USAN experience” with substances that have a chiral center and explains nomenclature rules for enantiomers and stereoisomers. We analyzed records of USAN adoptions between 1999 and 2004 to see how many chiral compounds were undergoing clinical development.
Substances with the same chemical formula but different structures are referred to as isomers. Those with the same connectivity are referred to as stereoisomers, and several types are relevant to pharmaceuticals.
Enantiomers are non-superimposable mirror images of one another. Compounds that are enantiomers are often described as chiral, a term that is derived from the Greek chiros, which means “handed.” They usually contain a chiral center, typically a carbon atom bound to four different atoms or groups. A compound may be chiral without the asymmetric carbon if it lacks an axis or plane of symmetry, but this scenario is uncommon.
Enantiomers cannot be separated by distillation, crystallization, or chromatography on columns packed with achiral materials. If the other reactants are achiral, both enantiomers will have identical reactivity. Their physical properties (e.g., dielectric constant, melting point, boiling point) are also the same.
Enantiomers do differ in how they rotate plane-polarized light. Compounds that rotate light clockwise are called dextrorotatory; those that rotate light counterclockwise are termed levorotatory. Dextrorotatory compounds are designated with the (+) descriptor in their chemical names; levorotatory compounds are designated with the (-) symbol. Before FDA regulations changed in 19921 and asymmetric synthesis and chiral separation technologies were widely used, pharmaceuticals were usually marketed as a mixture of the dextrolevatory and levorotatory isomers, called a racemic mixture.
An enantiomer may also be specified by describing its stereochemistry using the Cahn-Ingold-Prelog convention, which assigns a priority to each substituent on the chiral center. This convention ranks atoms attached to a chiral carbon according to atomic number—the higher the atomic number, the higher the priority. If two atoms attached to the central carbon have the same atomic number (e.g., 2 carbon atoms), one moves along the chain until there is a difference between the atoms; the group in which the higher atomic-number atom is found closest to the chiral carbon receives the higher priority. Thus, an ethyl group receives a higher priority than a methyl group.
Once the substituents have been ranked, the molecule is visualized in an orientation that places the lowest-priority substituent, often a hydrogen atom, directly behind the chiral center. If the remaining substituents decrease in priority around the chiral center in a clockwise direction, the substance is the R (rectus) enantiomer. If the direction is counterclockwise, the substance is an S (sinister) enantiomer.
A chiral substance is described by its stereochemical descriptor (R, S), optical properties (+,-) , and its chemical name. The chemical names of most stereoisomers that receive USANs follow this scheme.
In the Fischer convention, configurations are described by the descriptors D and L. These are assigned by comparison with a reference molecule, glyceraldehyde, using projection formulas. If the molecule has the same configuration as D-glyceraldehyde, it is assigned this configuration; molecules with the L designation have the same configuration as L-glyceraldehyde. The application of D and L descriptors is limited to carbohydrates or carbohydrate-like substances, and is seldom used in USAN adoption statements.
Diastereomers include all stereoisomers that are not mirror images of one another. Diastereomers have different physical properties and chemical reactivity—different melting points, boiling points, affinities for chromatographic materials. This means they can be chemically separated by methods such as crystallization or HPLC columns packed with achiral materials.
When a molecule has more than one chiral center, it may or may not be chiral and optically active. For a diastereomer with multiple chiral centers to be chiral, there must be no plane or point of symmetry within the molecule.
Geometric isomers of alkenes, in which atoms and groups are arranged asymmetrically about a double bond, are also diastereomers. When they are designated as cis- or –trans, this is based on judgments about the similarity of substituents attached to the double bond. Another system to describe stereochemistry about the double bond is based on the Cahn-Ingold-Perlog convention used to rank atoms and groups. The Z descriptor (from zusammen, German for “together”) is used when the 2 substituents with the highest priority are arranged on the same side of the double bond. The E descriptor (from entgegen, German for “opposing”) is applied when they are on opposite sides.
In inorganic transition metal complexes, cis-, trans-, fac-, and mer- isomers are the result of arrangements of ligands around a metal ion. A typical example is cisplatin and its derivatives. Like organic diastereomers, inorganic diastereomers have different physical and chemical properties.
Isomerism and Pharmacologic Properties
Although enantiomers have the same reactivity toward achiral compounds, they may react differently with chiral substances. Thus, one enantiomer of a chiral drug may bind to a receptor's asymmetric active site, while the other binds weakly or not at all. Many biological molecules (e.g., enzymes, receptors) are chiral or assymetric. Consequently, different enantiomers often have very different pharmacologic properties.
If the nontherapeutic enantiomer has undesirable reactivity, there is a potential for serious, even tragic consequences. The marketing and subsequent withdrawal of thalidomide in Europe is the classic example. When this drug, a glutamic acid derivative, was marketed in the 1950's, it was thought to be so safe it was prescribed as a treatment for morning sickness in pregnant women. At physiologic pH, thalidomide is a racemic mixture of the R and S isomers. The R isomer causes sedation. The S isomer is tetrogenic and caused severe birth defects after only one dose.5-7 Because the R and S isomers interconvert at physiologic pH, both isomers are present in the body.7
USAN Rules for Naming Enantiomers
Although pharmaceuticals are chiral, names for new chemical entities do not routinely specify the stereoisomeric form of the molecule named. However, if the stereochemical configuration has been determined, this information is presented in the chemical name(s) and reflected in the structural formula. A USAN can, therefore, identify the racemic mixture (e.g., carnitine, ibuprofen), the levo isomer (e.g., remoxipride), or the dextro form (e.g., butopamine).
If, after a USAN is obtained for a substance, a new name is needed for a different enantiomer or the racemic form, specific prefixes are added to the USAN of the substance that has already been named. The USAN Council names enantiomers or racemic mixtures of an existing substance based on structural relationships to the first substance, not on pharmacologic properties or activity.
To modify an existing USAN for a new enantiomer, the following prefixes are added:8
- For the racemate, the rac-/race- prefix is used (e.g., racemethioning, racepinephrine, ractopamine).
- For the levo rotatory form, the S isomer, the lev-/levo- prefix is used (e.g., levocarnitine, levamisole, levcromakalim, levdobutamine).
- For the levorotatory form but for the R isomer [R(-) isomer] the ar- prefix is added to the base name.
- For the dextrorotatory form, the R isomer, the dex-/dextro- prefix is used (e.g. dexamisole, dexibuprofen, dextroamphetamine, dexverapamil, dexfosfoserine, dexniguldipine).
- For the dextro rotary form but for the S isomer [S(+)-isomer], the es- prefix is added to the base name (e.g. escitalopram).
As the USAN Council works closely with the INN Expert Committee to standardize nomenclature internationally, the USAN Council rules for naming enantiomers are similar to those used to generate International Nonproprietary Names (INNs).
The USANC recognizes that isomers or racemates of an existing substance may have different pharmacology, biological activity, or indications. However, the established nomenclature scheme for enantiomers or racemates of chiral compounds is based on their structural relationship to the parent compound. Consequently, enantiomers do not receive a stem that is different from that of the parent substance, based on different activity or a different indication.
USAN Procedures for Naming Diastereomers. Because diastereomers can be differentiated by their reaction chemistry and physical properties (i.e., melting point, chromatographic affinity), they are named as individual compounds. Such compounds may or may not be under development for the same indication.
Stereochemistry of the Substances Receiving USANs
Paper copies of adoptions statements are available for all adoptions since the inception of the USAN program in the 1960's.
Chiral Switches. When a pharmaceutical manufacturer develops a single-enantiomer product from a drug marketed as a racemic mixture, that is called a “chiral switch.” The single-enantiomer product receives additional patent protection and a new generic name based on the USAN and WHO rules for naming enantiomers. The manufacturer markets the single-enantiomer drug as a new product, with a different trade name. Chiral switches have been used by manufacturers to extend the life of blockbuster drugs.9,10
Table 1: Commonly Prescribed Drugs and Their Enantiomeric Switches
esoxybutynin (Phase III)
(S)-amlodipine (Phase II)
dexbudesonide (Biological testing)
dexsotalol (Phase III)
ketoprofen (Actron, Orudis)
dexlansoprazole (status unknown)
desvenlafaxine (Phase III)
arformoterol (Phase III)
zopiclone (Imovane in Canada)
modafinil (Provigil, Alertec, etc.)
Several chiral switches extended the life of manufacturers’ existing blockbuster drugs (Table 1), and this has been cited as an important factor in their development of chiral switches. 10-13 When the original developer of a blockbuster did not patent individual enantiomers, third-party companies, such as Sepracor, have been able to develop the single isomer and enter into licensing agreements with the company that marketed the racemic mixture.
We determined the number of chiral switches was determined for each year between 1999 and 2005 through an analysis of USAN adoption records (Table 2). All compounds named with a prefix of lev-, ar-, dex-, es-, or rac- were classified as chiral switches. The total number of adoptions for each year was determined by tabulating the adoption statements issued during that year.
Pharmaceutical-industry analysts and journalists have suggested that manufacturers will increasingly rely on chiral switches to fuel growth.3,4 However, analysis of the number of chiral switches that have received USANs since 1999 suggests otherwise. Chiral switches accounted for a significant number of USANs in 2002 (8 percent) but their numbers have declined since then. Currently, relatively are reaching the IND stage with plans to further continue clinical development for the US market, as judged by the number that received USANs in 2004 and so far in 2005. Since all new drugs introduced in the US must receive USANs, and since drugs normally receive generic names 1-2 years before they reach the market, fewer new chiral switches should become commercially available in the next few years.
Table 2: Enantiomeric Switches Per Year, 1999-2005
Number of Chiral Switches
Number of Adoptions
* As of September 30, 2005.
One reason for the declining number of chiral switches in recent years may be that fewer drugs have been reaching the market—and becoming blockbusters—as racemic mixtures. As will be discussed in the next section, relatively few racemic mixtures are being developed. Thus, there are fewer new racemic drugs on which to base chiral switches.
Because the presence of a second enantiomer in racemic mixtures is associated with a potential for drug-drug interactions, severe adverse reactions, and market withdrawals, the use of stereochemically pure drugs is thought to offer advantages and was recommended by the FDA in its 1992 guidelines. Chiral switches may have an improved therapeutic index through increased potency and selectivity, decreased side effects, an improved onset and duration of effect, and decreased drug-drug interactions.14
Additionally, if insurers are less willing to pay for the added cost of single-enantiomer drugs, pharmaceutical companies might develop fewer of them. The value of specific enantiomeric switches has been debated.15,16 Published research may suggests some benefits for asingle enantiomer treatment, but others say the benefits do not justify the added costs, which can be substantial.9,17-20 As an example, an unscientific survey of Chicago-area pharmacies found that esomeprazole was considerably more expensive than omeprazole: for a 30-day supply, the average cost was $22 for omeprazole 20 mg, $155 for esomeprazole 40 mg, and $145 for esomeprazole 20 mg.
USAN Adoptions—Chiral Compounds
To evaluate the prevalence of chiral and single-enantiomer compounds in pharmaceutical pipelines, we classified the substances that received USANs between 2000 and 2004 according to structures. Small molecules were classified as achiral, chiral but a mix of enantiomers or diastereomers, and chiral with one enantiomer or diastereomer. Other categories included polymers, peptides, proteins, monoclonal antibodies, and oligomers.
We inspected the structure and chemical names published in each statement. Small molecules included organic compounds and inorganic compounds that were not simple ionic salts or solid-state compounds (e.g., NaCl, Fe2O3), polymers, proteins, peptides, antibodies, or oligonucleotides. Chirality and the presence of one or multiple enantiomers (or diastereomers) was based on what was shown in chemical structure drawings and the chemical names. Before publication, all adoption statements are reviewed by an expert chemist with a thorough knowledge of structural organic chemistry and chemical nomenclature. Substances comprised of amino acids that existed as proteins in nature or recombinant proteins were classified as proteins. Peptides included short peptide chains, peptides containing non-natural amino acids, and other peptide-derived substances. Similarly, oligonucleotides included derivatives with non-naturally occurring moieties.
Table 3: USAN Adoptions, by Type of Substance
Chiral, racemic mixture
Chiral, single enantiomer or diastereomer
Polymers, including contact lens materials
Most compounds that received a USAN in 2004 were small molecules. Of these, roughly one-third were achiral. Among the substances that had a chiral center, almost all were a single enantiomer (or a single diastereomer for multiple chiral centers)—accounting for almost half of all substances that received a USAN. Only a very small number of chiral compounds were being developed as a racemic mixture.
A significantly larger fraction of substances receiving USANs (47 percent) were chiral, single enantiomer (or diastereomer) substances in 2004 than in 2000 (27 percent). However, the fraction of single-enantiomer compounds did not steadily or consistently increase each year during this time. The fraction of chiral substances marketed as racemic drugs, remained small during 2000-2004. Generally, fewer achiral compounds than compounds with chiral centers received USANs. The fraction of substances receiving USANs that were biologics or polymers has remained relatively constant.
Worldwide sales of single-enantiomer drugs were estimated to have grown at a rate of >13 percent in 2000, to $147.2 billion, accounting for 40 percent and 36 percent of all drug sales in 2000 and 2001.21 Drugs approved by the FDA during 1998-2001 were classified as follows: 52 percent achiral, 30 percent single enantiomers/diastereomers with several chiral centers, 7 percent single enantiomers with one chiral center, 7 percent racemates, and 4 percent multiple diastereomers.22
The fact that almost half of all drugs receiving USANs were chiral, single enantiomer or diastereomer drugs suggests that these will continue to play an important role in the pharmaceutical business. The declining number of enantiomeric switches receiving USANs indicates that there are now fewer of these in clinical development than in the recent past, and that fewer of these may reach the market in the coming years. While the number of chiral substances named increased between 2000 and 2004, this may be a trend, a cyclic variation, or a sporadic occurrence.
- Food and Drug Administration. FDA’s policy statement for the development of new stereoisomeric drugs. US Food and Drug Administration [policy document] Available at www.fda.gov/cder/guidance/stereo.htm. Fed Reg. 1992;22:249.
- Stinson Sc. Counting on chirality. Chem Eng News. 2000;76(38):83-104.
- Rouhi AM. Chiral business. Chem Eng News. 2003;81(18):45-55.
- RB-188 US Prescription Drug Market: Strategies for Sustained Growth. Norwalk, CT: Business Communications Company Inc.; 2004.Available at www.bccresearch.com.
- Lenz W. Thalidomide and congenital anomalies. Lancet. 1962;1:45.
- Tseng S, Pak G, Washenik K, et al. Rediscovering thalidomide: a review of its mechanism of action, side effects, and potential. J Am Acad Dermatol. 1996:35;969-979.
- Stirling DI. Pharmacology of thalidomide. Semin Hematol. 2000;37(1 suppl 3):5-14.
- The USAN Handbook. Chicago, IL: US Adopted Names Program; 1999.
- Agranat I, Caner H. Putting chirality to work: the strategy of chiral switches. Nat Rev Drug Discov. 2002;1:753-768.
- Agranat I, Caner H. Intellectual property and chirality of drugs. Drug Disc Today. 1999;4:313-329.
- Racemic Switch Update. World Market and Technology Assessment: Optically Active Chemical Compound Report. 11th ed. Technology Catalyst Interantional Corp. Falls Church, VA, 2001.
- Handley DA. The therapeutic advantages achieved through single-isomer drugs. Pharm News. 1999;6:11-15.
- Cannarsa MJ. Racemic Switches: historical perspectives and current status. Chem Oggi/ChemToday. 1999;17:28-32.
- Tucker GT. Chiral switches. Lancet. 2000;385:1085-1087.
- Waldek B. Three-dimensional pharmacology, a subject ranging from ignorance to overstatements.Pharmacol and Toxicol. 2003; 93:203-210.
- Therapeutics Initiative University of British Columbia. Do single stereoisomer drugs provide value? Therapeutics Let. 2002 (June-Sept);45-46.
- Rohss K, Lind T, Wilder Smith C.Eur J Clin Pharmacol. 2004;60:531-539.
- Sanchez C. Bogeso KP, Ebert B, et al. escitalopram versus citalopram: the surprising role of the R-enantiomer.Psychopharmacology. 2004;174:163-176.
- Masilamani S, Ruppelt SC. Escitalopram (Lexapro) for depression. Am Fam Phys. 2003; 68: 2234-2236.
- Davies NM, Teng XW. Importance of chirality in drug therapy and pharmacy profile: implications for psychiatry. Adv Pharmacy. 2003; 1: 242-252.
- Stinson SC. Chiral chemistry. Chem Eng News. 2001;79(X):45-56.
- Miller SP. FDA perspectives on quality control for chiral pharmaceuticals. 135th Int Symp Chiral Discrimination. 2001. Abstract 4316.