Τόμος 9 (1995) – Τεύχος 1 – Άρθρο 1 – Επιθεώρηση Κλινικής Φαρμακολογίας και Φαρμακοκινητικής-Διεθνής Έκδοση – Volume 9 (1995) – Issue 1 – Article 1 – Epitheorese Klinikes Farmakologias και Farmakokinetikes-International Edition

 

Title Chirality and new drug development in 1995
Authors Charalampos T. Plessas1, Stavros T. Plessas2 and Achilles Benakis3

1. PHARMAKON-Press, Department of Scientific Informations, Athens, Greece

2. Laboratory of Physiology, Department of Nursing, University of Athens, Athens, Greece

3. Laboratory of Drug Metabolism, Department of Pharmacology, School of Medicine, University of Geneva, Geneva, Switzerland

Citation Plessas, C.T., Plessas, S.T., Benakis, A.: Chirality and new drug development in 1995, Epitheorese Klin. Farmakol. Farmakokinet. 9(1): 3-20 (1995)
Publication Date 1995
Full Text Language English
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Keywords Chirality, stereoisomers, pharmacology, pharmacokinetics, drug development, enantiomeric separation, chromatography on chiral stationary phases, chromatography on chiral mobile phases, capillary zone electrophoresis, preparation, cost-benefit analysis, regulatory requirements.
Other Terms review article
Summary All living organisms are constituted by ordered asymmetric biomolecules, such as proteins (receptors, enzymes, antibodies), carbohydrates, neurotransmitters, hormones etc., due to the special geometry of one or more of their carbon atoms. The asymmetry is not only restricted to the biogenic compounds; a great number of xenobiotics, including drugs, thought to be monosubstances, are in fact racemic mixtures of two or more diastereoisomers. These stereoisomers (including enantiomers) may interact in different ways with biological structures and, therefore, may exhibit widely different pharmacodynamics and pharmacokinetic properties. These considerations justify the current trends, in pharmaceutical industry as well as in regulatory authorities, to develop the eutomer, i.e. the single enantiomer characterised by the most favourable pharmacological profile. The possibility to produce the eutomer is facilitated by the availability of new technologies for the stereoselective synthesis and separation of individual enantiomers from the racemic mixtures; these technologies include chiral stationary phases, chiral mobile phases and capillary zone electrophoresis. However, any decision to develop the eutomer should be based on careful consideration of production and development costs and actual therapeutic advantages especially in terms of improved safety.
References 1. Plessas C.T., Plessas S.T., Benakis A.: Drug stereochemistry and stereoselectivity: Implications in clinical pharmacology. Epitheor. Kith. Farmakoi. Farmakokinet, Int. Ed. 2: 67-84 (1988)

 2. Avgerinos A., Hutt A.J.: Stereoselective drug metabolism: Pharmacological and pharmacokinetic consequences. Epitheor. Klin. Farmakoi. Farmakokinet., Int. Ed. 4: 131-147 (1990)

 3. Campbell D.B.: Stereoselectivity in clinical pharmacokinetics and drug development. Eur. J. Drug Metabol. Pharmacokinet. 15: 109-125 (1990)

 4. Ariens E.J.: Stereoselectivity, a natural aspect of molecular biology: A blind spot in clinical pharmacology and pharmacokinetics. Eur. J. Drug Metabol. Pharmacokinet. 13: 307 (1988)

 5. Cahn R.S., Ingold C.D., Prelog V.: Specification of molecular chirality. Angew. Chem. Int. Ed. 5: 385-415 (1966)

 6. Testa B.: Mechanisms of chiral recognition in xenobiotic metabolism and drug-receptor interactions. Chirality 1: 7-9 (1989)

 7. Blackwood J.E., Giles P.M.: Chemical Abstracts, Stereochemical nomentclature of organic substances in the ninth collective period (1972-1976). J. Chem. Inf. Comp. Sci. 15: 67-72 (1975)

 8. Testa B.: Mechanisms of chiral recognition in pharmacology. The Easson-Stedman model revisited. Acta Pharm. Nord. 2: 137-144 (1990)

 9. Pifferi G., Perucca E.: The cost benefit ratio of enantiomeric drugs. Eur. J. Drug Metabol. Pharmacokinet. 20: 15-25 (1995)

 10. Testa B., Carrupt P.-A., Gal J.: The so-called interconversion of stereoisomeric drugs: An attempt at clarification. Chirality 5 :105-111 (1993)

 11. Testa B., Carrupt P.-A., Christiansen L., Christoffersen P., Reist M.: Chirality in drug research: Stereomania, stereophobia, or stereophilia? In: Trends in Drug Research (V. Claassen, ed.), Vol. 20, pp. 1-8, Elsevier, Amsterdam, 1993

12. Yang S.K., Lu X.-L.: Resolution and stability of oxazepam enantiomers. Chirality 4: 443-446 (1992)

 13. Knoche B., Blaschke G.: Racemization of thalidomide in vitro. Third International Symposium on Chiral Discrimination, Tubingen, 4-8 October 1992, Abstract No 144

 14. Plessas C.T., Plessas S.T., Benakis A.: Clinical pharmacokinetics of drug enantiomers. Epitheor. Klin. Farmakol. Farmakokinet. El. Ed. 7: 86-110 (1989)

 15. Williams K., Lee E.: Importance of drug enantiomers in clinical pharmacology. Drugs 30: 333-354 (1985)

 16. Lee E., Williams K.: Chirality. Clinical pharmacokinetic and pharmacodynamic considerations. Clin. Pharmacokinet. 18: 339-345 (1990)

 17. Plessas C.T., Plessas S.T., Benakis A., Karayannakos P.: Genetically determined polymorphisms in drug acetylation and oxidation. Epitheor. Klin. Farmakol. Farmakokinet. Int. Ed. 5: 39-57 (1991)

 18. Nation R.J.: Chirality in new drug development. Clin. Pharmacokinet. 27: 249-255 (1994)

 19. Francotte E.: Contribution of preparative chromatographic resolution to the investigation of chiral phenomena. J. Chromatogr. A 666: 565-601 (1994)

 20. Allenmark S.G.: Chromatographic enantioseparation. Methods and Applications. Ellis Horwood, Chichester, 1988

 21. M. Zief, L.J. Crane (eds): Chromatographic Chiral Separations. Marcel Dekker, New York, 1988

 22. Hutt A.J., Caldwell J.: Stereospecific analytical methodology. In: Metabolism of Xenobiotics (J.W.Gorrod, H. Oelschlager, J. Caldwell, eds), pp. 335-344, Taylor and Francis, London, 1988

 23. Allenmark S.G.: In: Chiral Separation by Liquid Chromatography (S. Ahuia, ed.), p. 471, ACS Symposium Series, Washington, 1991

24. I.W. Wainer (ed.): Drug Stereochemistry, Analytical Methods and Pharmacology. 2nd Edition, Marcel Dekker, New York, Basel, 1993

25. A.M. Krstulovic (ed.): Chiral Separations by HPLC. Applications to pharmaceutical compounds. Ch. 11, Ellis Horwood, Chichester, 1989

 26. Francotte E., Junker-Buchheit A.: Preparative chromatographic separation of enantiomers. J. Chromatogr. 576: 1-45 (1992)

 27. Blaschke G., Bröker W., Fraenkel W.: Chromatographic separation of racemates. 15. HPLC separation of enantiomers on silica gel-bound optically active polyamides. Angew. Chem. 98: 808-810 (1986)

 28. Shaw C.J., Sanfilippo P.J., MacNaily J.H., Park S.A., Press J.B.: Analytical and preparative highperformance liquid chromatographic separation of thienopyran enantiomers. J. Chromatogr. 631: 173-175 (1993)

 29. Bruche G., Mosiand A., Kinkel J.N.: Stereoisomeric flavor compounds 65. Preparative resolution of the enantiomers of chiral dihydrofuranoses by recycling chromatography. JHRC 16: 254-265 (1993)

 30. Vermeulen N.P.E., Testa B,: Principles of stereoselective analysis of pesticides. Ιn: Stereoselectivity of Pesticides: Biological and Chemical Problems (E.J. Ariens, J.J.S. van Rensen, W. Welling, (eds), pp.375-407, Elsevier, Amsterdam, 1988

 31. Welch C.J.: Evolution of chiral stationary phase design in the Pirkle laboratories. J. Chromatogr. 666: 3-26 (1994)

 32. Pirkle W.H., Welch C.J.: Chromatographic separation of enantiomers of acylated amines by chiral stationary phases. J. Org. Chem. 49:138-140 (1984)

 33. Pirkle W.H., Pochapsky T.C.: Generation of extreme selectivity in chiral recognition. J. Chromatogr. 369: 175-177 (1986)

 34. Pirkle W., Welch C.J.: An improved chiral stationary phase for the chromatographic separation of underivatized naproxen enantiomers. J. Liq. Chromatogr. 15: 1947-1955 (1992)

 35. Pirkle W.H., Burke J.A.: Chiral stationary phase designed for β-blockers J. Chromatogr. 557: 173-185 (1991)

 36. Welch C.J.: An improved method for the direct chromatographic resolution of abscisic acid enantiomers. Chiratity 5: 569-572 (1994)

 37. Pirkle W.H., Ho Hyun M., Bank B.: A rational approach to the design of highly-effective chiral stationary phases. J. Chromatogr. 316: 585-604 (1984)

 38. Pirkle W.H., Ho Hyun M.: Reversed-phase chromatographic resolution of N-(3,5-dinitrobenzoyl)-α-amino acids on chiral stationary phases J. Chromatogr. 322: 287-297 (1985)

 39. Davankov V.A., Bochkow A.S., Belov Y.P.: Ligand exchange chromatography. XV. Resolution of α-amino acids on reversed phase gels coated with N-decyl-L-histidine. J. Chromatogr. 218: 547-557 (1981)

 40. Däppen R., Arm H., Meyer V.R.: Applications and limitations of commercially available chiral stationary phases for HPLC. J. Chromatogr. Chromatogr. Rev. 373: 1-20 (1986)

 41. Dobashi A., Hara S.: Chiroselective complexation based on hydrogen bonds for the resolution of Dand L-amino acid derivatives by silica gel liquid chromatography. J. Chromatogr. 267: 11-17 (1983)

 42. Dobashi A., Dobashi Y., Hara S.: Enantioselectivity of hydrogen bond association in liquid-solid chromatography. J. Liq. Chromatogr. (Special issue on optical resolution in Liquid Chromatography) 9: 243-267 (1986)

 43. Dobashi Y., Hara, S.: Extended scope of chiral recognition applying hydrogen bond associations in nonaqueous media: (R.R)-N.N’-diisopropyltartramide (DIPTA) as a widely applicable resolving agent. J. Am. Chem. Soc. 107: 3406-3411 (1985)

 44. Petersson C., Stuurman H.W.: Direct separation of enantiomer of ephedrine and some analogues by reversed-phase liquid chromatography using (+)-di-nbutyltartrate as liquid stationary phase. J. Chromatogr. Sci. 22. 441-443 (1984)

 45. Debowski H., Sybilska D.: Separation of isomeric alkylbenzenes in RP-HPLC through α– and β-cyclodextrin inclusion complexes. J. Chromatogr. 353: 409-416 (1986)

 46. Lepage J.N., Lindner W., Davies G., Seitz D.E., Karger B.L.: Resolution of the optical isomers of dansyl amino acids by reversed-phase liquid chromatography with optically active metal chelate additives. Anal. Chem. 51: 433-435 (1979)

 47. Gelber L.R., Neumeyer J.L.: Determination of the enantiomeric purity of levodopa, methyl dopa, carbidopa and tryptophan by use of chiral mobile phase HPLC. J. Chromatogr. 257: 317-326 (1983)

 48. Lam S., Karmen A.: Resolution of optical isomers as the mixed chelate Cu(ll)-complexes by reversed phase chromatography. J. Liq. Chromatogr. 9: 291-311 (1986)

49. Petersson C., Schill G.: Separation of enantiomers in ion-pair chromatographic systems. J. Liq. Chromatogr. (Special issue on optical resolution in Liquid Chromatography) 9: 269-290 (1986)

 50. Petersson C., Schilf G.: Chiral resolution of aminoalcohols by ion-pair chromatography. Chromatographia 16: 192-197 (1982)

 51. Petersson C.: Chromatographic separation of enantiomers of acids with quinine as diural counterion. J. Chromatogr. 316: 553-567 (1984)

 52. Lindner W.: Indirect separation of enantiomers by liquid chromatography. In: Chromatographic Chiral Separations (M. Zief, L.J. Crane, eds), p. 283, Marcel Dekker, New York, 1988

 53. Ward T.J.: Chiral media for capillary electrophoresis. Anal. Chem. 66: 633A-640A (1994)

 54. H. Engelhardt et al. (eds): Kapillarelektrophoresis, Methoden und Möglichkeiten. Vieweg, 1994

55. R. Kuhn et al. (eds): Capillary Electrophoresis: Principles and Practice. Springer Verlag, 1993

 56. Hoffmann K.J., Renberg L., Bäärnhielm C.: Stereoselective disposition of RS-tocainide in man. Eur. J. Drug Metabol. Pharmacokinet 9: 215-222 (1984)

 57. Silber B., Riegelman S.: Stereospecific assay for (-)- and (+)-propranolol in human and dog plasma. J. Pharmacol. Exp. Ther. 215: 643-648 (1980)

58. Maître J.M., Boss G., Testa B.: H{LC separation of the enantiomers of anti-inflammatory 2-aryl-propionates: Suitability of the method for in vitro studies. J. Chromatogr. 229: 397-403 (1984)

 59. Lee E.J.D., Williams K.M., Graham G.G., Day R.O., Champion G.D.: Liquid chromatographic determination and plasma concentration profile of optical isomers of ibuprofen in humans. J. Pharm. Sci. 73: 1542-1544 (1984)

 60. Gübitz G., Mibelleyes S.: Optical resolution of β-blocking agents by TLC and HPLC as diastereomeric R-(-)-1-(1-naphtyl)ethylureas. J.  Chromatogr. 314: 462-466 (1984)

 61. Buck R.H., Krummen K.: HPLC determination of enantiomeric amino acids and amino alcohols after derivatization with ophthaldialdehyde and various chiral mercaptans: Application to peptide hydrolysates. J. Chromatogr. 387: 255-265 (1987)

 62. Blaschke G.: Chromatographic resolution of chiral drugs on polyamides and cellulose triacetate. J. Liq. Chromatogr. 9: 341-368 (1986)

63. Tucker G.P.: Stereoisomers in clinical practice: the good, the bad and the ugly. Int Pharm. J. 7(Suppl. 1): S117 (1993)

 64. Smith R.L., Caldwell J.: Racemates: towards a New Year resolution? Trends Pharmacol. Sci. 9: 75-77 (1988)

 65. Weissinger J.: Considerations in the development of stereoisomeric drugs: FDA viewpoint. Drug Info J.23: 663-667 (1989)

 66. Cartwright A.C.: Stereochemistry and safety, efficacy and quality issues: genesis of new regulations. Drug Info J. 24: 115-116 (1990)

 67. Kumkumian C.S.: Regulatory considerations concerning stereoisomers in drug products. Drug Info J. 24: 125-127

68. Pharmacological Biochemistry Group Colloquium: Chirality and its importance in drug development. Biochem. Soc. Trans. 19: 443-475 (1991)

 69. Lennard M.S.: Clinical pharmacology through the looking glass: reflections on racemate vs enantiomer debate. Br. J. Clin. Pharmacol. 31: 623-625 (1991)

 70. Ariens E.J.: Racemic therapeutics – ethical and regulatory aspects. Eur. J. Clin. Pharmacol. 41: 89-93 (1991)

 71. Gross M., Cartwright A., Campbell B., et al.: Regulatory requirements for chiral drugs. Drug Info J. 27: 453-457 (1993)

72. Department of Health and Human Services, Food and Drug Administration. FDA’s policy statement for the development of new stereoisomeric drugs. Federal Register 57: 22249 (1992)

 73. US Policy on new stereoisomeric drugs. The Regulatory Affairs Journal, Dec.: 1001-1004 (1993)

 74. DeCamp W.H.: Chiral drugs: The FDA perspective on manufacturing and control. J. Pharm. Biomed. Anal. 11: 1167-1172 (1993)

 75. CPMP Working Parties on Quality, Safety and Efficacy of Medicinal Products. Commission of the European Communities: Note for guidance: investigation of chiral active substances. III/3501/91-EN

 76. Seiler J.P.: Chiral drugs – the view of the Swiss Intercantonal Office for the Control of Medicines. Drug Info J. 27: 485-489 (1993)

 77. Rauws A.G., Groen K.: Current Regulatory (Draft Guidance on Chiral Products: Canada, EEC, Japan, United States. Chirality 6: 71-75 (1994)

 78. Shindo H., Caldwell J.: Regulatory aspects of the development of chiral drugs in Japan: a status report. Chirality 3: 91-93 (1991)

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