Chemistry:Chiral switch

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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]

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

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 drug Chiral switch (Unichiral drugs) [29][33] Pharmacological action Main benefit(s) claimed
Ibuprofen (S)-(+)-Ibuprofen; Dexibuprofen Anti-inflammatory Faster onset; low adverse effect profile
Ofloxacin (S)-(-)-Ofloxacin; Levofloxacin Antibactereial increased potency
Ketoprofen (S)-(+)-Ketoprofen; Dexketoprofen Anti-inflammatory Faster onset
Salbutamol/ Albuterol (R)-(-)-Albuterol; Levalbuterol Bronchodilator Reduction in side effects; improved tolerability profile
Omeprazole (S)-(-)-Omepazole; Esomeprazole Proton pump inhibitor Increased activation; less variable metabolism
Bupivacaine (S)-(-)-Bupivacaine; Levobupivacine Local anesthetic Decreased risk of cardiotoxicity
Cetrizine (R )-(-)-Cetrizine; Levocetirizine Antihistamine Increased potency; decreased side-effects
Citalopram (S)-(-)-Citalopram; Escitalopram Antidepressant Faster onset of action; reduction in side effects and improved tolerability profile
Ketamine (S)-Ketamine Anaesthetic Increased 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 drug Chiral switch Pharmacological action Comments
Fluoxetine (R)-Fluoxetine Antidepressant Significant increase in QTC ; Abnormal heart rhythms; Aborted the program[34]
Fenfluramine (S)-Fenfluramine; Dexphenfluramine Antiobesity Valvular heart disease and Pulmonary hypertension; withdrawn worldwide,1997.[35][36]
Labetalol Dilevalol Beta blocker Increased hepatotoxicity[37]
Propranolol S(-)-Propranolol Beta blocker Unexpected 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 drug Metabolite switch Pharmacological action Main claimed benefit(s)
Terfenadine Fexofenadine Antihistaminic Decreased cardiotoxicity
Halofantrine Desbutythalofantrine Antimalarial Decreased cardiotoxicity
Cisapride Norcisapride Prokinetic Increased 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

References

  1. ↑ 1.0 1.1 "The strategy of enantiomer patents of drugs". Drug Discovery Today 15 (5–6): 163–170. March 2010. doi:10.1016/j.drudis.2010.01.007. PMID 20116449. 
  2. ↑ "Trends in the development of chiral drugs". Drug Discovery Today 9 (3): 105–110. February 2004. doi:10.1016/s1359-6446(03)02904-0. PMID 15038394. 
  3. ↑ 3.0 3.1 "Intellectual property and chirality of drugs". Drug Discovery Today 4 (7): 313–321. July 1999. doi:10.1016/s1359-6446(99)01363-x. PMID 10377509. 
  4. ↑ 4.0 4.1 4.2 4.3 "Putting chirality to work: the strategy of chiral switches". Nature Reviews. Drug Discovery 1 (10): 753–768. October 2002. doi:10.1038/nrd915. PMID 12360254. 
  5. ↑ "Obtaining a Granted Patent". Patents for Chemicals, Pharmaceuticals, and Biotechnology. Oxford University Press. 2016-12-22. doi:10.1093/oso/9780199684731.003.0009. ISBN 978-0-19-968473-1. 
  6. ↑ "Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology". European Journal of Clinical Pharmacology 26 (6): 663–668. 1984. doi:10.1007/bf00541922. PMID 6092093. 
  7. ↑ "Stereochemistry: a source of problems in medicinal chemistry". Medicinal Research Reviews 6 (4): 451–466. 1986. doi:10.1002/med.2610060404. PMID 3534485. 
  8. ↑ "Stereoselectivity of bioactive xenobiotics. A pre-Pasteur attitude in medicinal chemistry, pharmacokinetics and clinical pharmacology". Biochemical Pharmacology 37 (1): 9–18. January 1988. doi:10.1016/0006-2952(88)90749-6. PMID 3276322. 
  9. ↑ "Racemic therapeutics--ethical and regulatory aspects". European Journal of Clinical Pharmacology 41 (2): 89–93. 1991. doi:10.1007/BF00265897. PMID 1743252. 
  10. ↑ "Enantioselective aspects of drug action and disposition: therapeutic pitfalls". Journal of Pharmaceutical Sciences 78 (9): 695–715. September 1989. doi:10.1002/jps.2600780902. PMID 2685226. 
  11. ↑ "Methods for the analysis of enantiomers of racemic drugs application to pharmacological and pharmacokinetic studies". Journal of Pharmacological and Toxicological Methods 29 (1): 1–9. February 1993. doi:10.1016/1056-8719(93)90044-f. PMID 8481555. 
  12. ↑ "Pharmacodynamic and pharmacokinetic differences between drug enantiomers in humans: an overview". Clinical Pharmacology and Therapeutics 40 (2): 125–133. August 1986. doi:10.1038/clpt.1986.150. PMID 3731675. 
  13. ↑ Chiral Separations by HPLC. Ellis Horwwod, Chichester. 1989. pp. 31–68. 
  14. ↑ "Racemic mixtures and single stereoisomers: Industrial concerns and issues in drug development". Chirality 3 (2): 94–98. 1991. doi:10.1002/chir.530030203. ISSN 0899-0042. 
  15. ↑ "Stereoselective drug disposition: potential for misinterpretation of drug disposition data". British Journal of Clinical Pharmacology 26 (6): 771–780. December 1988. doi:10.1111/j.1365-2125.1988.tb05318.x. PMID 3242583. 
  16. ↑ "Pharmacokinetic parameters obtained with racemates". Trends in Pharmacological Sciences 7: 155–158. 1986. doi:10.1016/0165-6147(86)90294-4. ISSN 0165-6147. 
  17. ↑ "Regulatory Requirements for Chiral Drugs". Drug Information Journal 27 (2): 453–457. 1993. doi:10.1177/009286159302700232. ISSN 0092-8615. 
  18. ↑ "Pharmacodynamics, pharmacokinetics and toxicity of ibuprofen enantiomers". Drugs of the Future 22 (12): 1347. 1997. doi:10.1358/dof.1997.022.12.711853. ISSN 0377-8282. 
  19. ↑ "The metabolic chiral inversion and dispositional enantioselectivity of the 2-arylpropionic acids and their biological consequences". Biochemical Pharmacology 37 (1): 105–114. January 1988. doi:10.1016/0006-2952(88)90762-9. PMID 3276314. 
  20. ↑ "Chiral drugs: an overview". International Journal of Biomedical Science 2 (2): 85–100. June 2006. doi:10.59566/IJBS.2006.2085. PMID 23674971. 
  21. ↑ The impact of stereochemistry on drug development and use. New York: Wiley. 1997. ISBN 0-471-59644-2. OCLC 35262289. https://www.worldcat.org/oclc/35262289. 
  22. ↑ 22.0 22.1 22.2 "Chiral switches". Lancet 355 (9209): 1085–1087. March 2000. doi:10.1016/s0140-6736(00)02047-x. PMID 10744105. 
  23. ↑ 23.0 23.1 "Single-enantiomer drugs: elegant science, disappointing effects". Clinical Pharmacokinetics 43 (5): 287–290. 2004. doi:10.2165/00003088-200443050-00002. PMID 15080762. 
  24. ↑ "Stereoisomeric Drugs: FDA'S Policy Statement and the Impact on Drug Development". Drug Development and Industrial Pharmacy 20 (2): 119–139. 1994. doi:10.3109/03639049409039080. ISSN 0363-9045. 
  25. ↑ "Development of chiral drug in an evolving regulatory environment". Regulatory Affairs 3: 483–494. 1991. 
  26. ↑ "CHIRAL DRUGS". Chemical & Engineering News Archive 71 (39): 38–65. 1993-09-27. doi:10.1021/cen-v071n039.p038. ISSN 0009-2347. 
  27. ↑ "CHIRAL DRUGS". Chemical & Engineering News Archive 73 (41): 44–546274. 1995-10-09. doi:10.1021/cen-v073n041.p044. ISSN 0009-2347. 
  28. ↑ "Regulatory Considerations concerning Stereoisomers in Drug Products". Drug Information Journal 24 (1): 125–127. 1990. doi:10.1177/009286159002400124. ISSN 0092-8615. 
  29. ↑ 29.0 29.1 Joseph, Gal; Lindner, Wolfgang (2006). Francotte, Eric. ed. "Chiral drugs from a historical point of view". In Chirality in drug research. Germany: Wiley-VCH Verlag GmbH & Co. pp. 3–26. ISBN 3-527-31076-2. 
  30. ↑ Gal, J (1998). "Problems of stereochemical nomenclature and terminology. The homochiral controversy. Its nature, origins, and a proposed solution". Enantiomer 3: 263–273. 
  31. ↑ "The market of chiral drugs: Chiral switches versus de novo enantiomerically pure compounds". Journal of Pharmaceutical and Biomedical Analysis 147: 323–340. January 2018. doi:10.1016/j.jpba.2017.07.008. PMID 28942107. 
  32. ↑ "Chiral Switch: Between Therapeutical Benefit and Marketing Strategy". Pharmaceuticals 15 (2): 240. February 2022. doi:10.3390/ph15020240. PMID 35215352. 
  33. ↑ "On the meaning and use of homochiral". Journal of Chromatography A 829 (1–2): 417–418. 1998. doi:10.1016/s0021-9673(98)00845-0. ISSN 0021-9673. 
  34. ↑ "Eli Lilly Pulls The Plug On Prozac Isomer Drug". Chemical & Engineering News Archive 78 (44): 8. 2000-10-30. doi:10.1021/cen-v078n044.p008. ISSN 0009-2347. 
  35. ↑ "Valvular heart disease associated with fenfluramine-phentermine". The New England Journal of Medicine 337 (24): 1772–1776. December 1997. doi:10.1056/nejm199712113372414. PMID 9411246. 
  36. ↑ Anonymous (1997). "Fenfluramine and dexfenfluramine withdrawn. Further cases of valvular heart disease". Current Problems in Pharmacovigilance 23: 13–14. 
  37. ↑ 37.0 37.1 "Pharmacologically active compounds in the environment and their chirality". Chemical Society Reviews 39 (11): 4466–503. November 2010. doi:10.1039/c000408c. PMID 20852776. http://opus.bath.ac.uk/21550/1/Kasprzyk%2DHordern_Chem_Soc_Rev_2010_39_11_4466.pdf. 
  38. ↑ "Impact of evergreening on patients and health insurance: a meta analysis and reimbursement cost analysis of citalopram/escitalopram antidepressants". BMC Medicine 10 (1): 142. November 2012. doi:10.1186/1741-7015-10-142. PMID 23167972.  CC BY-SA icon.svg Text was copied from this source, which is available under a Creative Commons Attribution 2.0 Generic (CC BY 2.0) license.
  39. ↑ "Escitalopram: superior to citalopram or a chiral chimera?". Psychotherapy and Psychosomatics 73 (1): 10–16. 2003-12-12. doi:10.1159/000074435. PMID 14665791. 
  40. ↑ "Chiral Switch: Between Therapeutical Benefit and Marketing Strategy". Pharmaceuticals 15 (2): 240. February 2022. doi:10.3390/ph15020240. PMID 35215352. 
  41. ↑ "Evergreening: a common practice to protect new drugs". Nature Biotechnology 29 (10): 876–878. October 2011. doi:10.1038/nbt.1993. PMID 21997625. http://nrs.harvard.edu/urn-3:HUL.InstRepos:8965556. 
  42. ↑ 42.0 42.1 42.2 "Inside the isomers: the tale of chiral switches" (in en). Australian Prescriber 27 (2): 47–49. 2004. doi:10.18773/austprescr.2004.039. https://www.nps.org.au/australian-prescriber/articles/inside-the-isomers-the-tale-of-chiral-switches-1. 
  43. ↑ D'Acquarica, Ilaria; Agranat, Israel (2023-01-17). "The Quest for Secondary Pharmaceuticals: Drug Repurposing/Chiral-Switches Combination Strategy" (in en). ACS Pharmacology & Translational Science 6 (2): 201–219. doi:10.1021/acsptsci.2c00151. ISSN 2575-9108. PMID 36798472. PMC 9926527. https://pubs.acs.org/doi/10.1021/acsptsci.2c00151. 

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