Chiral switch

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Levofloxacin as an example of a chiral switch Levofloxacin chiral switch.svg
Levofloxacin as an example of a chiral switch

A chiral switch is a chiral drug that has already approved as racemate but has been re-developed as a single enantiomer. [1] [2] The term chiral switching was introduced by Agranat and Caner in 1999 [3] to describe the development of single enantiomers from racemate drugs. For example, levofloxacin is a chiral switch of racemic ofloxacin. The essential principle of a chiral switch is that there is a change in the status of chirality. [4] In general, the term chiral switch is preferred over racemic switch because the switch is usually happening from a racemic drug to the corresponding single enantiomer(s). It is important to understand that chiral switches are treated as a selection invention. [3] A selection invention is an invention that selects a group of new members from a previously known class on the basis of superior properties. [5] To express the pharmacological activities of each of the chiral twins of a racemic drug two technical terms have been coined eutomer and distomer. [6] [7] The member of the chiral twin that has greater physiological activity is referred to as the eutomer and the other one with lesser activity is referred to as distomer. The eutomer/distomer ratio is called the eudisimic ratio and reflects the degree of enantioselectivity of the biological activity. [8]

Contents

In case of stereoselectivity in action only one of the components in the racemic mixture is truly active (eutomer). The other isomer, the distomer, should be regarded as impurity or isomeric ballast [9] not contributing to the effects aimed at. It is well documented that the pharmacologically inactive isomer (distomer) may contribute to the toxic or adverse effects of the drugs. There is a wide spectrum of possibilities of distomer actions, many of which are confirmed experimentally. [10] [11] Sometimes the single enantiomer version lacks certain side-effects that the racemate exhibits. And where the two enantiomers are sufficiently different in pharmacological effects, it may be possible to get a patent on one or both isomers (for instance, as in the case of propoxyphene). The chiral twins of propoxyphene are separately sold by Eli Lilly and company. Dextropropoxyphene is an analgesic agent (Darvon) and levopropoxyphene an effective antitussive (Novrad). [12] [13] Interestingly the reversed trade names of the drugs, DARVON and NOVRAD, also reflect the chemical mirror-image relationship. A positive consequence of this redesigning approach is that it has given a new life to an old drug, minimizing or avoiding the undesirable side-effect profile. Whether to go in for a chiral switch is normally made on a case-by-case basis. A pragmatic solution could be in favor of a decision-tree approach, incorporating various factors such as pharmacodynamic, pharmacokinetic, toxicological profile of the enantiomers, enantiomer-enantiomer interaction potential, safety, efficacy, risk-benefit ratio, chiral inversion, distomer liability, physicochemical properties, cost of separation and production, quality control criteria, marketing edge, etc. [14] [15] [16] [17]

The concept

The chiral switch concept [4] is illustrated in the diagram. This chiral switch is from (±)-ibuprofen to (S)-(+)-ibuprofen (dexibuprofen). The nonsteroidal anti-inflammatory drug (NSAID) ibuprofen was the first chiral drug of the NSAID class to be switched to the single-enantiomer version in 1994. The switch was done based on the fact that the (S)-ibuprofen, the eutomer, was over 100-fold more potent as an inhibitor of cycloxygenase-1 (COX-1) enzyme than (R)-ibuprofen. [18] Moreover, ibuprofen, when administered as the racemate, the active (R)-enantiomer undergoes partial unidirectional chiral inversion (approximately 60%) to the (S)-enantiomer. Therefore, the use of the single (S)-ibuprofen was expected to give faster onset of action at a lower dosage. [19] Further, while choosing the chiral drug candidate for a chiral switch one should take a look at the chiral inversion tendency of the molecule. For instance, thalidomide, the sedative drug, undergoes bidirectional chiral inversion or racemization in biological systems. [20] [21] [4] In such cases chiral switching efforts will be pointless.

The chiral-switch concept The Chiral Switch Concept.png
The chiral-switch concept

Advantages

There are several possible potential benefits to chiral switching or chiral specific drugs. [22] These include:

  1. An improved (less complex, more selective) pharmacodynamic profile
  2. A higher therapeutic index (improved safety margin)
  3. Less complex pharmacokinetic profile, less complex drug interactions
  4. Less complex relationship between plasma concentration and effect  
  5. More rational therapeutic drug monitoring
  6. Expose the patient to less body load and thus reduce metabolic/renal/hepatic drug load

The chiral switching approach has sometimes resulted in failures and disappointments. [23]

Regulatory environment

The roles of regulatory agencies also continue to evolve with respect to the development of chiral switches. An interesting concept brought up in the FDA policy is that of "bridging studies". [24] [25] [26] [27] When a sponsor/innovator seeks to develop a single enantiomer from a racemic drug, the regulatory agencies demand them to conduct bridging studies. Bridging studies are tests (pharmacological and toxicological evaluations) to connect what is known about the already approved racemate and what is unknown about the single enantiomer under study, without going back to square one as for a completely new chemical entity. The intent of the bridging studies is to make sure that the companies are not scarifying some protective effect conferred by the other" isomer when they develop a chiral drug as single enantiomer rather than a racemate. "Bridging" procedure will help to reduce the number of studies required on the "new" enantiopure drug. [28]

Examples

Launched

Chiral switch, a re-engineering approach, has enabled in the remarketing of a number of racemic drugs as chiral specific enantiomer products. Chiral switching strategy is the way most blockbuster drugs have entered the market as enantiopure drugs. A more appropriate term may be unichiral. [29] [30] But the alternate route is de novo (anew) synthesis of chiral specific drugs. [31] The chiral switches may have the same, very similar, therapeutic indications as the original racemic drug. But, there are instances where new indications for the old drug have been reported. The table below gives a brief list of launched chiral switches. [22] [32]

Racemic drugChiral switch (Unichiral drugs) [29] [33] Pharmacological actionMain benefit(s) claimed
Ibuprofen(S)-(+)-Ibuprofen; Dexibuprofen Anti-inflammatoryFaster onset; low adverse effect profile
Ofloxacin(S)-(-)-Ofloxacin; Levofloxacin Antibactereialincreased potency
Ketoprofen(S)-(+)-Ketoprofen; Dexketoprofen Anti-inflammatoryFaster onset
Salbutamol/ Albuterol(R)-(-)-Albuterol; Levalbuterol BronchodilatorReduction in side effects; improved tolerability profile
Omeprazole(S)-(-)-Omepazole; Esomeprazole Proton pump inhibitorIncreased activation; less variable metabolism
Bupivacaine(S)-(-)-Bupivacaine; Levobupivacine Local anestheticDecreased risk of cardiotoxicity
Cetrizine(R )-(-)-Cetrizine; Levocetirizine AntihistamineIncreased potency; decreased side-effects
Citalopram(S)-(-)-Citalopram; Escitalopram AntidepressantFaster onset of action; reduction in side effects and improved tolerability profile
Ketamine (S)-Ketamine AnaestheticIncreased potency and tolerance; faster recovery

Failed/aborted

The re-evaluation of single enantiomers not without problems. The chiral switches of fluoxetine and fenfluramine are classical examples. [4] The development of (R )-fluoxetine was terminated after patients developed abnormal heart rhythms. The chiral switch of fenfluramine, dexfenfluramine was withdrawn from world marker due to pulmonary hypertension. The table below enumerates couple of chiral switches aborted or withdrawn due stereochemically engineered toxicity.

Racemic drugChiral switchPharmacological actionComments
Fluoxetine(R)-FluoxetineAntidepressantSignificant increase in QTC ; Abnormal heart rhythms; Aborted the program [34]
Fenfluramine(S)-Fenfluramine; DexphenfluramineAntiobesityValvular heart disease and Pulmonary hypertension; withdrawn worldwide,1997. [35] [36]
LabetalolDilevalolBeta blockerIncreased hepatotoxicity [37]
PropranololS(-)-PropranololBeta blockerUnexpected reduction of beta-blocking activity [37]

Evergreening

Evergreening refers to the various strategies whereby owners (innovators/sponsors) of pharmaceutical products use patent laws and minor drug modifications to extend their monopoly privileges on the drug. [38] An enantiomer patent is another form of evergreening based on a chiral switch strategy. [1] Single-enantiomer drugs represent more than 50% of the top-selling 100 drugs worldwide. [39] There are some studies which go to suggest that drug companies employ chiral switching for life-cycle management/patent protection of the parent racemic drug and also as a marketing strategy. [23] [40] Pharmaceutical companies support evergreening practices. [41] Some chiral switches are performed to re-start the patent clock for a medication without reducing side effects or improving efficacy. [42] A high price can then continue to be charged for a medication. [42] Examples include citalopram and escitalopram, and omeprazole and esomeprazole. In both these medications, proposed theoretical benefits were used to market the enantiopure drugs, without any clinical trials being conducted to provide evidence that the racemic drugs improved patient centered outcomes. [42]

Metabolite switches

This idea, drug to metabolite switching, is an extension of the chiral switch concept. The purpose of the switching is to develop an active metabolite which will be devoid of the side-effects and have an improved therapeutic profile compared to the parent chiral drug. Some examples of chiral drug to metabolite switches, [22] (those in the market and others under investigation) include terfenadine to fexofenadine, halofantrine to desbutylhalofantrine, and cisapride to norcisapride. A summary is presented in the table below.

Chiral drugMetabolite switchPharmacological actionMain claimed benefit(s)
TerfenadineFexofenadineAntihistaminicDecreased cardiotoxicity
HalofantrineDesbutythalofantrineAntimalarialDecreased cardiotoxicity
CisaprideNorcisaprideProkineticIncreased efficacy; decreased cardiotoxicity

Drug repurposing/chiral-switches

Drug repurposing and chiral switches are part of the secondary pharmaceuticals strategy. [43] The COVID-19 pandemic has increased drug repurposing and this approach suggests combining the two strategies for better results. This combination strategy is not new, but has not been intentional until now. The combination strategy may improve pharmacology, patents, reduce costs, speed up approval times, and increase regulatory exclusivities. The benefits of the combination strategy include superior pharmacology, stronger patents, shorter approval times, and more exclusivity.  Patenting this combination strategy is not considered evergreening, product hopping, or me-too. This perspective calls for a comprehensive search for worldwide-approved racemic drugs to be repurposed and combined with chiral switches.

See also

Related Research Articles

<span class="mw-page-title-main">Stereochemistry</span> Subdiscipline of chemistry

Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on the relationships between stereoisomers, which by definition have the same molecular formula and sequence of bonded atoms (constitution), but differ in the geometric positioning of the atoms in space. For this reason, it is also known as 3D chemistry—the prefix "stereo-" means "three-dimensionality".

In chemistry, a racemic mixture or racemate is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates.

<span class="mw-page-title-main">Ibuprofen</span> Medication treating pain, fever, and inflammation

Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used to relieve pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus arteriosus in a premature baby. It can be used orally or intravenously. It typically begins working within an hour.

<span class="mw-page-title-main">Enantiomer</span> Stereoisomers that are nonsuperposable mirror images of each other

In chemistry, an enantiomer – also called optical isomer, antipode, or optical antipode – is one of two stereoisomers that are nonsuperposable onto their own mirror image. Enantiomers of each other are much like one's right and left hands; without mirroring one of them, hands cannot be superposed onto each other. It is solely a relationship of chirality and the permanent three-dimensional relationships among molecules or other chemical structures: no amount of re-orientiation of a molecule as a whole or conformational change converts one chemical into its enantiomer. Chemical structures with chirality rotate plane-polarized light. A mixture of equal amounts of each enantiomer, a racemic mixture or a racemate, does not rotate light.

<span class="mw-page-title-main">Tramadol</span> Medication of the opioid type, patented 1972

Tramadol, sold under the brand name Ultram among others, is an opioid pain medication and a serotonin–norepinephrine reuptake inhibitor (SNRI) used to treat moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an hour. It is also available by injection. It is available in combination with paracetamol (acetaminophen).

In chemistry, racemization is a conversion, by heat or by chemical reaction, of an optically active compound into a racemic form. This creates a 1:1 molar ratio of enantiomers and is referred to as a racemic mixture. Plus and minus forms are called Dextrorotation and levorotation. The D and L enantiomers are present in equal quantities, the resulting sample is described as a racemic mixture or a racemate. Racemization can proceed through a number of different mechanisms, and it has particular significance in pharmacology as different enantiomers may have different pharmaceutical effects.

<span class="mw-page-title-main">Chirality (chemistry)</span> Geometric property of some molecules and ions

In chemistry, a molecule or ion is called chiral if it cannot be superposed on its mirror image by any combination of rotations, translations, and some conformational changes. This geometric property is called chirality. The terms are derived from Ancient Greek χείρ (cheir) 'hand'; which is the canonical example of an object with this property.

The molecular configuration of a molecule is the permanent geometry that results from the spatial arrangement of its bonds. The ability of the same set of atoms to form two or more molecules with different configurations is stereoisomerism. This is distinct from constitutional isomerism which arises from atoms being connected in a different order. Conformers which arise from single bond rotations, if not isolatable as atropisomers, do not count as distinct molecular configurations as the spatial connectivity of bonds is identical.

<span class="mw-page-title-main">4-Methylaminorex</span> Group of stereoisomers

4-Methylaminorex is a stimulant drug of the 2-amino-5-aryloxazoline class that was first synthesized in 1960 by McNeil Laboratories. It is also known by its street name "U4Euh" ("Euphoria"). It is banned in many countries as a stimulant.

<span class="mw-page-title-main">Flunoxaprofen</span> Chemical compound

Flunoxaprofen, also known as Priaxim, is a chiral nonsteroidal anti-inflammatory drug (NSAID). It is closely related to naproxen, which is also an NSAID. Flunoxaprofen has been shown to significantly improve the symptoms of osteoarthritis and rheumatoid arthritis. The clinical use of flunoxaprofen has ceased due to concerns of potential hepatotoxicity.

<span class="mw-page-title-main">Dexibuprofen</span> Chemical compound

Dexibuprofen is a nonsteroidal anti-inflammatory drug (NSAID). It is the active dextrorotatory enantiomer of ibuprofen. Most ibuprofen formulations contain a racemic mixture of both isomers.

An enantiopure drug is a pharmaceutical that is available in one specific enantiomeric form. Most biological molecules are present in only one of many chiral forms, so different enantiomers of a chiral drug molecule bind differently to target receptors. Chirality can be observed when the geometric properties of an object is not superimposable with its mirror image. Two forms of a molecule are formed from a chiral carbon, these two forms are called enantiomers. One enantiomer of a drug may have a desired beneficial effect while the other may cause serious and undesired side effects, or sometimes even beneficial but entirely different effects. The desired enantiomer is known as an eutomer while the undesired enantiomer is known as the distomer. When equal amounts of both enantiomers are found in a mixture, the mixture is known as a racemic mixture. If a mixture for a drug does not have a 1:1 ratio of its enantiomers it is a candidate for an enantiopure drug. Advances in industrial chemical processes have made it economical for pharmaceutical manufacturers to take drugs that were originally marketed as a racemic mixture and market the individual enantiomers, either by specifically manufacturing the desired enantiomer or by resolving a racemic mixture. On a case-by-case basis, the U.S. Food and Drug Administration (FDA) has allowed single enantiomers of certain drugs to be marketed under a different name than the racemic mixture. Also case-by-case, the United States Patent Office has granted patents for single enantiomers of certain drugs. The regulatory review for marketing approval and for patenting is independent, and differs country by country.

The eudysmic ratio represents the difference in pharmacologic activity between the two enantiomers of a drug. In most cases where a chiral compound is biologically active, one enantiomer is more active than the other. The eudysmic ratio is the ratio of activity between the two. A eudysmic ratio significantly differing from 1 means that they are statistically different in activity. Eudisimic ratio (ER) reflects the degree of enantioselectivity of the biological systems. For example, (S)-propranolol meaning that (S)-propranolol is 130 times more active than its (R)-enantiomer.

<span class="mw-page-title-main">Chirality</span> Difference in shape from a mirror image

Chirality is a property of asymmetry important in several branches of science. The word chirality is derived from the Greek χείρ (kheir), "hand", a familiar chiral object.

<span class="mw-page-title-main">Levomethadone</span> Synthetic opioid

Levomethadone, sold under the brand name L-Polamidon among others, is a synthetic opioid analgesic and antitussive which is marketed in Europe and is used for pain management and in opioid maintenance therapy. In addition to being used as a pharmaceutical drug itself, levomethadone is the main therapeutic component of methadone.

<span class="mw-page-title-main">Indacrinone</span> Chemical compound

Indacrinone is a loop diuretic. It can be used in patients of gout with hypertension as an antihypertensive because it decreases reabsorption of uric acid, while other diuretics increase it.

Chemical compounds that come as mirror-image pairs are referred to by chemists as chiral or handed molecules. Each twin is called an enantiomer. Drugs that exhibit handedness are referred to as chiral drugs. Chiral drugs that are equimolar (1:1) mixture of enantiomers are called racemic drugs and these are obviously devoid of optical rotation. The most commonly encountered stereogenic unit, that confers chirality to drug molecules are stereogenic center. Stereogenic center can be due to the presence of tetrahedral tetra coordinate atoms (C,N,P) and pyramidal tricoordinate atoms (N,S). The word chiral describes the three-dimensional architecture of the molecule and does not reveal the stereochemical composition. Hence "chiral drug" does not say whether the drug is racemic, single enantiomer or some other combination of stereoisomers. To resolve this issue Joseph Gal introduced a new term called unichiral. Unichiral indicates that the stereochemical composition of a chiral drug is homogenous consisting of a single enantiomer.

Chiral inversion is the process of conversion of one enantiomer of a chiral molecule to its mirror-image version with no other change in the molecule.

Chiral analysis refers to the quantification of component enantiomers of racemic drug substances or pharmaceutical compounds. Other synonyms commonly used include enantiomer analysis, enantiomeric analysis, and enantioselective analysis. Chiral analysis includes all analytical procedures focused on the characterization of the properties of chiral drugs. Chiral analysis is usually performed with chiral separation methods where the enantiomers are separated on an analytical scale and simultaneously assayed for each enantiomer.

<span class="mw-page-title-main">Ravi Bhushan</span> Indian chemist (born 1953)

Ravi Bhushan was a Professor of Chemistry at Indian Institute of Technology Roorkee who worked in the areas of natural products chemistry, protein chemistry, and chiral analysis by liquid chromatography.

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