Chiral switch

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]

  1. ^ Agranat I, Wainschtein SR (March 2010). "The strategy of enantiomer patents of drugs". Drug Discovery Today. 15 (5–6): 163–170. doi:10.1016/j.drudis.2010.01.007. PMID 20116449.
  2. ^ Caner H, Groner E, Levy L, Agranat I (February 2004). "Trends in the development of chiral drugs". Drug Discovery Today. 9 (3): 105–110. doi:10.1016/s1359-6446(03)02904-0. PMID 15038394.
  3. ^ a b Agranat I, Caner H (July 1999). "Intellectual property and chirality of drugs". Drug Discovery Today. 4 (7): 313–321. doi:10.1016/s1359-6446(99)01363-x. PMID 10377509.
  4. ^ Agranat I, Caner H, Caldwell J (October 2002). "Putting chirality to work: the strategy of chiral switches". Nature Reviews. Drug Discovery. 1 (10): 753–768. doi:10.1038/nrd915. PMID 12360254. S2CID 1543301.
  5. ^ Grubb PW, Thomsen PR, Hoxie T, Wright G (2016-12-22). "Obtaining a Granted Patent". Patents for Chemicals, Pharmaceuticals, and Biotechnology. Oxford University Press. doi:10.1093/oso/9780199684731.003.0009. ISBN 978-0-19-968473-1.
  6. ^ Ariëns EJ (1984). "Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology". European Journal of Clinical Pharmacology. 26 (6): 663–668. doi:10.1007/bf00541922. PMID 6092093. S2CID 30916093.
  7. ^ Ariëns EJ (1986). "Stereochemistry: a source of problems in medicinal chemistry". Medicinal Research Reviews. 6 (4): 451–466. doi:10.1002/med.2610060404. PMID 3534485. S2CID 36115871.
  8. ^ Ariëns EJ, Wuis EW, Veringa EJ (January 1988). "Stereoselectivity of bioactive xenobiotics. A pre-Pasteur attitude in medicinal chemistry, pharmacokinetics and clinical pharmacology". Biochemical Pharmacology. 37 (1): 9–18. doi:10.1016/0006-2952(88)90749-6. PMID 3276322.
  9. ^ Ariëns EJ (1991). "Racemic therapeutics--ethical and regulatory aspects". European Journal of Clinical Pharmacology. 41 (2): 89–93. doi:10.1007/BF00265897. PMID 1743252. S2CID 12768116.
  10. ^ Jamali F, Mehvar R, Pasutto FM (September 1989). "Enantioselective aspects of drug action and disposition: therapeutic pitfalls". Journal of Pharmaceutical Sciences. 78 (9): 695–715. doi:10.1002/jps.2600780902. PMID 2685226.
  11. ^ Wright MR, Jamali F (February 1993). "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. doi:10.1016/1056-8719(93)90044-f. PMID 8481555.
  12. ^ Drayer DE (August 1986). "Pharmacodynamic and pharmacokinetic differences between drug enantiomers in humans: an overview". Clinical Pharmacology and Therapeutics. 40 (2): 125–133. doi:10.1038/clpt.1986.150. PMID 3731675. S2CID 33537650.
  13. ^ Ariens EJ (1989). Krstulovic AM (ed.). Chiral Separations by HPLC. Ellis Horwwod, Chichester. pp. 31–68.
  14. ^ Cayen MN (1991). "Racemic mixtures and single stereoisomers: Industrial concerns and issues in drug development". Chirality. 3 (2): 94–98. doi:10.1002/chir.530030203. ISSN 0899-0042.
  15. ^ Evans AM, Nation RL, Sansom LN, Bochner F, Somogyi AA (December 1988). "Stereoselective drug disposition: potential for misinterpretation of drug disposition data". British Journal of Clinical Pharmacology. 26 (6): 771–780. doi:10.1111/j.1365-2125.1988.tb05318.x. PMC 1386594. PMID 3242583.
  16. ^ Walle T, Walle UK (1986). "Pharmacokinetic parameters obtained with racemates". Trends in Pharmacological Sciences. 7: 155–158. doi:10.1016/0165-6147(86)90294-4. ISSN 0165-6147.
  17. ^ Gross M, Cartwright A, Campbell B, Bolton R, Holmes K, Kirkland K, et al. (1993). "Regulatory Requirements for Chiral Drugs". Drug Information Journal. 27 (2): 453–457. doi:10.1177/009286159302700232. ISSN 0092-8615. S2CID 72629140.