Chiral switch

The essential principle of a chiral switch is that there is a change in the status of chirality.{{cite journal | vauthors = Agranat I, Caner H, Caldwell J | title = Putting chirality to work: the strategy of chiral switches | journal = Nature Reviews. Drug Discovery | volume = 1 | issue = 10 | pages = 753–768 | date = October 2002 | pmid = 12360254 | doi = 10.1038/nrd915 | s2cid = 1543301 }} 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.

To express the pharmacological activities of each of the chiral twins of a racemic drug, two technical terms have been coined: eutomer and distomer.{{cite journal | vauthors = Ariëns EJ | title = Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology | journal = European Journal of Clinical Pharmacology | volume = 26 | issue = 6 | pages = 663–668 | date = 1984 | pmid = 6092093 | doi = 10.1007/bf00541922 | s2cid = 30916093 }}{{cite journal | vauthors = Ariëns EJ | title = Stereochemistry: a source of problems in medicinal chemistry | journal = Medicinal Research Reviews | volume = 6 | issue = 4 | pages = 451–466 | date = 1986 | pmid = 3534485 | doi = 10.1002/med.2610060404 | s2cid = 36115871 }} 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.{{cite journal | vauthors = Ariëns EJ, Wuis EW, Veringa EJ | title = Stereoselectivity of bioactive xenobiotics. A pre-Pasteur attitude in medicinal chemistry, pharmacokinetics and clinical pharmacology | journal = Biochemical Pharmacology | volume = 37 | issue = 1 | pages = 9–18 | date = January 1988 | pmid = 3276322 | doi = 10.1016/0006-2952(88)90749-6 }}

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{{cite journal | vauthors = Ariëns EJ | title = Racemic therapeutics--ethical and regulatory aspects | journal = European Journal of Clinical Pharmacology | volume = 41 | issue = 2 | pages = 89–93 | date = 1991 | pmid = 1743252 | doi = 10.1007/BF00265897 | s2cid = 12768116 }} not contributing to the intended effects. 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.{{cite journal | vauthors = Jamali F, Mehvar R, Pasutto FM | title = Enantioselective aspects of drug action and disposition: therapeutic pitfalls | journal = Journal of Pharmaceutical Sciences | volume = 78 | issue = 9 | pages = 695–715 | date = September 1989 | pmid = 2685226 | doi = 10.1002/jps.2600780902 }}{{cite journal | vauthors = Wright MR, Jamali F | title = Methods for the analysis of enantiomers of racemic drugs application to pharmacological and pharmacokinetic studies | journal = Journal of Pharmacological and Toxicological Methods | volume = 29 | issue = 1 | pages = 1–9 | date = February 1993 | pmid = 8481555 | doi = 10.1016/1056-8719(93)90044-f }} 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, where Dextropropoxyphene is an analgesic agent (Darvon) and levopropoxyphene an effective antitussive (Novrad).{{cite journal | vauthors = Drayer DE | title = Pharmacodynamic and pharmacokinetic differences between drug enantiomers in humans: an overview | journal = Clinical Pharmacology and Therapeutics | volume = 40 | issue = 2 | pages = 125–133 | date = August 1986 | pmid = 3731675 | doi = 10.1038/clpt.1986.150 | s2cid = 33537650 }}{{Cite book| vauthors = Ariens EJ |title=Chiral Separations by HPLC|publisher=Ellis Horwwod, Chichester|year=1989| veditors = Krstulovic AM |pages=31–68}} Interestingly the reversed trade names of the drugs, DARVON and NOVRAD, also reflect the chemical mirror-image relationship.

File:The Chiral Switch Concept.png

The chiral switch concept 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.{{Cite journal| vauthors = Mayer JM, Testa B |date=1997|title=Pharmacodynamics, pharmacokinetics and toxicity of ibuprofen enantiomers |journal=Drugs of the Future|volume=22|issue=12|page=1347|doi=10.1358/dof.1997.022.12.711853|issn=0377-8282}} 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.{{cite journal | vauthors = Caldwell J, Hutt AJ, Fournel-Gigleux S | title = The metabolic chiral inversion and dispositional enantioselectivity of the 2-arylpropionic acids and their biological consequences | journal = Biochemical Pharmacology | volume = 37 | issue = 1 | pages = 105–114 | date = January 1988 | pmid = 3276314 | doi = 10.1016/0006-2952(88)90762-9 }}

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.{{cite journal | vauthors = Nguyen LA, He H, Pham-Huy C | title = Chiral drugs: an overview | journal = International Journal of Biomedical Science | volume = 2 | issue = 2 | pages = 85–100 | date = June 2006 | doi = 10.59566/IJBS.2006.2085 | pmid = 23674971 | pmc = 3614593 }}{{Cite book |title=The impact of stereochemistry on drug development and use |date=1997 |publisher=Wiley | vauthors = Aboul-Enein HY, Wainer IW |isbn=0-471-59644-2 |location=New York |oclc=35262289}} In such cases chiral switching efforts will be pointless.

A positive consequence of a chiral switch approach is that it has given a new life to an old drug, minimizing or avoiding the undesirable side-effect profile. Whether to proceed in 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.{{Cite journal |vauthors=Cayen MN |date=1991 |title=Racemic mixtures and single stereoisomers: Industrial concerns and issues in drug development |journal=Chirality |volume=3 |issue=2 |pages=94–98 |doi=10.1002/chir.530030203 |issn=0899-0042}}{{cite journal |vauthors=Evans AM, Nation RL, Sansom LN, Bochner F, Somogyi AA |date=December 1988 |title=Stereoselective drug disposition: potential for misinterpretation of drug disposition data |journal=British Journal of Clinical Pharmacology |volume=26 |issue=6 |pages=771–780 |doi=10.1111/j.1365-2125.1988.tb05318.x |pmc=1386594 |pmid=3242583}}{{Cite journal |vauthors=Walle T, Walle UK |date=1986 |title=Pharmacokinetic parameters obtained with racemates |journal=Trends in Pharmacological Sciences |volume=7 |pages=155–158 |doi=10.1016/0165-6147(86)90294-4 |issn=0165-6147}}{{Cite journal |display-authors=6 |vauthors=Gross M, Cartwright A, Campbell B, Bolton R, Holmes K, Kirkland K, Salmonson T, Robert J |date=1993 |title=Regulatory Requirements for Chiral Drugs |journal=Drug Information Journal |volume=27 |issue=2 |pages=453–457 |doi=10.1177/009286159302700232 |issn=0092-8615 |s2cid=72629140}}

There are several possible potential benefits to chiral switching or chiral specific drugs.{{cite journal | vauthors = Tucker GT | title = Chiral switches | journal = Lancet | volume = 355 | issue = 9209 | pages = 1085–1087 | date = March 2000 | pmid = 10744105 | doi = 10.1016/s0140-6736(00)02047-x | s2cid = 30715334 }} These include:

1. Improved (less complex, more selective) pharmacodynamic profile
2. 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.{{cite journal | vauthors = Mansfield P, Henry D, Tonkin A | title = Single-enantiomer drugs: elegant science, disappointing effects | journal = Clinical Pharmacokinetics | volume = 43 | issue = 5 | pages = 287–290 | date = 2004 | pmid = 15080762 | doi = 10.2165/00003088-200443050-00002 | s2cid = 31664339 }}

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".{{Cite journal| vauthors = Tomaszewski J, Rumore MM |date=1994|title=Stereoisomeric Drugs: FDA'S Policy Statement and the Impact on Drug Development |journal=Drug Development and Industrial Pharmacy|volume=20|issue=2|pages=119–139|doi=10.3109/03639049409039080|issn=0363-9045}}{{Cite journal| vauthors = Gross M |date=1991|title=Development of chiral drug in an evolving regulatory environment|journal=Regulatory Affairs|volume=3|pages=483–494}}{{Cite journal| vauthors = Stinson SC |date=1993-09-27|title=CHIRAL DRUGS |journal=Chemical & Engineering News Archive|volume=71|issue=39|pages=38–65|doi=10.1021/cen-v071n039.p038|issn=0009-2347}}{{Cite journal| vauthors = Stinson SC |date=1995-10-09|title=CHIRAL DRUGS |journal=Chemical & Engineering News Archive|volume=73|issue=41|pages=44–546274|doi=10.1021/cen-v073n041.p044|issn=0009-2347}} 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.{{Cite journal| vauthors = Kumkumian CS |date=1990|title=Regulatory Considerations concerning Stereoisomers in Drug Products |journal=Drug Information Journal|volume=24|issue=1|pages=125–127|doi=10.1177/009286159002400124|s2cid=72604547|issn=0092-8615}}

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.{{Cite book |last1=Joseph |first1=Gal |title="Chiral drugs from a historical point of view". In Chirality in drug research |last2=Lindner |first2=Wolfgang |publisher=Wiley-VCH Verlag GmbH & Co |year=2006 |isbn=3-527-31076-2 |editor-last=Francotte |editor-first=Eric |location=Germany |pages=3–26}}{{Cite journal |last=Gal |first=J |date=1998 |title=Problems of stereochemical nomenclature and terminology. The homochiral controversy. Its nature, origins, and a proposed solution |journal=Enantiomer |volume=3 |pages=263–273}} But the alternate route is de novo (anew) synthesis of chiral specific drugs.{{cite journal | vauthors = Calcaterra A, D'Acquarica I | title = The market of chiral drugs: Chiral switches versus de novo enantiomerically pure compounds | journal = Journal of Pharmaceutical and Biomedical Analysis | volume = 147 | pages = 323–340 | date = January 2018 | pmid = 28942107 | doi = 10.1016/j.jpba.2017.07.008 | s2cid = 6922311 }} 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.{{cite journal | vauthors = Hancu G, Modroiu A | title = Chiral Switch: Between Therapeutical Benefit and Marketing Strategy | journal = Pharmaceuticals | volume = 15 | issue = 2 | page = 240 | date = February 2022 | pmid = 35215352 | pmc = 8877306 | doi = 10.3390/ph15020240 | doi-access = free }}

The re-evaluation of single enantiomers not without problems. The chiral switches of fluoxetine and fenfluramine are classical examples. 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.

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.{{cite journal | vauthors = Alkhafaji AA, Trinquart L, Baron G, Desvarieux M, Ravaud P | title = Impact of evergreening on patients and health insurance: a meta analysis and reimbursement cost analysis of citalopram/escitalopram antidepressants | journal = BMC Medicine | volume = 10 | issue = 1 | page = 142 | date = November 2012 | pmid = 23167972 | pmc = 3520785 | doi = 10.1186/1741-7015-10-142 | doi-access = free }} 50px Text was copied from this source, which is available under a [https://creativecommons.org/licenses/by/2.0/ Creative Commons Attribution 2.0 Generic (CC BY 2.0)] license. An enantiomer patent is another form of evergreening based on a chiral switch strategy. Single-enantiomer drugs represent more than 50% of the top-selling 100 drugs worldwide.{{cite journal | vauthors = Svensson S, Mansfield PR | title = Escitalopram: superior to citalopram or a chiral chimera? | journal = Psychotherapy and Psychosomatics | volume = 73 | issue = 1 | pages = 10–16 | date = 2003-12-12 | pmid = 14665791 | doi = 10.1159/000074435 | s2cid = 2777719 }} 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.{{cite journal | vauthors = Hancu G, Modroiu A | title = Chiral Switch: Between Therapeutical Benefit and Marketing Strategy | journal = Pharmaceuticals | volume = 15 | issue = 2 | page = 240 | date = February 2022 | pmid = 35215352 | pmc = 8877306 | doi = 10.3390/ph15020240 | doi-access = free }} Pharmaceutical companies support evergreening practices.{{cite journal | vauthors = Gaudry KS | title = Evergreening: a common practice to protect new drugs | journal = Nature Biotechnology | volume = 29 | issue = 10 | pages = 876–878 | date = October 2011 | pmid = 21997625 | doi = 10.1038/nbt.1993 | s2cid = 19402161 | url = http://nrs.harvard.edu/urn-3:HUL.InstRepos:8965556 | url-access = subscription }} Some chiral switches are performed to re-start the patent clock for a medication without reducing side effects or improving efficacy.{{Cite journal| vauthors = Somogyi A, Bochner F, Foster D |title=Inside the isomers: the tale of chiral switches |journal=Australian Prescriber |year=2004|volume=27|issue=2|pages=47–49|url=https://www.nps.org.au/australian-prescriber/articles/inside-the-isomers-the-tale-of-chiral-switches-1|language=en|doi=10.18773/austprescr.2004.039 |doi-access=free|hdl=2440/39339|hdl-access=free}} A high price can then continue to be charged for a medication. 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.

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, (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.

Drug repurposing and chiral switches are part of the secondary pharmaceuticals strategy.{{Cite journal |last1=D'Acquarica |first1=Ilaria |last2=Agranat |first2=Israel |date=2023-01-17 |title=The Quest for Secondary Pharmaceuticals: Drug Repurposing/Chiral-Switches Combination Strategy |journal=ACS Pharmacology & Translational Science |volume=6 |issue=2 |language=en |pages=201–219 |doi=10.1021/acsptsci.2c00151 |pmid=36798472 |pmc=9926527 |issn=2575-9108}} 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.

• Chiral drugs
• Chirality
• Enantiopure drug
• Chiral inversion

{{Reflist}}

• {{Commonscatinline|Chiral switch}}

Category:Stereochemistry

Category:Enantiopure drugs