1 / 72

Drug Chirality : Past , Present & Future (?)

Drug Chirality : Past , Present & Future (?). Andrew J. Hutt. Department of Pharmacy, King’s College London. Stereochemistry Concerned with the three dimensional spatial arrangement of the atoms within a molecule. Stereoisomers

Télécharger la présentation

Drug Chirality : Past , Present & Future (?)

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.


Presentation Transcript

  1. Drug Chirality : Past , Present & Future (?) Andrew J. Hutt. Department of Pharmacy, King’s College London.

  2. Stereochemistry Concerned with the three dimensional spatial arrangement of the atoms within a molecule. • Stereoisomers Compounds with the same molecular connectivity but differ in the spatial arrangement of their constituent atoms or groups. • Enantiomers Stereoisomers which are non-superimposable mirror images of one another. • Diastereoisomers Stereoisomers which are not enantiomeric.

  3. Chiros – Greek Handed

  4. (-)-(R)-ibuprofen (+)-(S)-ibuprofen Stereoisomers of Ibuprofen

  5. Stereogenic S & P centres

  6. Stereoisomers of Phenylpropanolamine

  7. Phenylpropanolamine: UK Confusion • Independent risk factor for hemorrhagic stroke in women1 • Withdrawn in the USA (FDA, Oct. 10, 2000) • (+)-norpseudoephedrine in European preparations;()-norephedrine in North America(Martindale 32nd; Pharm J, Nov. 11, 2000) • ()-norephedrine in USA and Europe; structure of norpseudoephedrine presented in the British Pharmacopoeia 2000 (Pharm J, Dec. 2, 2000) 1Kernan WN, et al. N Engl J Med. 2000;343:1826-1832.

  8. Methaqualone enantiomers

  9. Differences between stereoisomers are hard to detect normally, but become much more marked in a chiral environment

  10. Chiral Biological Macromolecules • Proteins • Enzymes • Structural elements of membranes • Receptors • Carbohydrates • Nucleic acids • Chiral “building blocks” of L-amino acids and D-carbohydrates.

  11. Helical structures

  12. Louis Pasteur 1822-95 Pasteur & Tartaric Acid • Physically – separation of enantiomorphous crystals sodium ammonium salts. • Biologically – fermentation using Penicillum glaucum; (+)-enantiomer, carbon source leaving the (-)-enantiomer. • Chemically – resolution of diastereoisomeric salts using the optically pure base cinchonicine.

  13. Chirality & Biology • Piutti (1886) - (+)-asparagine has a sweet taste while the natural (-)- enantiomer is insipid. • Pasteur (1886) - “--- this difference due to the presence of an optically active substance in the nervous mechanism of taste --” • Regarded as the first mention of stereoselectivity of a receptor (Holmstedt, 1990).

  14. 1866 - 1926 Arthur R. Cushny & “Chiral” Pharmacology • (-)-Hyoscyamine almost exactly twice as active as atropine [(±)- hysocyamine] (1904). • (-)-Adrenaline twice the potency of (±)-adrenaline as a vasoconstrictor (1908); (-)-enantiomer 12-15 fold more potent than (+)-adrenaline on sympathetic vessels (1909). • Biological Relations of Optically Isomeric Substances (1926)

  15. Cushny & “Chiral” Pharmacology • Believed that the “receptor” was chiral and combined with the enantiomers of the drug to produce diastereoisomeric drug – receptor complexes. • “---- difference in action lies not in the facility with which the chemical combination is formed, but in the physical characteristics of the resultant compound” (Cushny, 1926).

  16. A D B C D' B' C ' Easson & Stedman (1933) Easson – Stedman ModelThree Point Interaction.

  17. Easson – Stedman : Prochiral Analog Two Site Interaction.

  18. Ogston (1948;1958) Ogston & Prochirality • Three point attachment Model to rationalise the observed stereoselectivity in the enzymatic transformation of symmetrical, prochiral, substrates. • A & A* are identical enantiotopic; if A’* is the catalytic site then A*, but not A will undergo transformation. • Static Model.

  19. No enantioselectivity x * Highly enantioselective or enantiospecific y Sokolov & Zefirov, 1991 “Rocking Tetrahedron” Model • Dynamic Model. • Substrate binds at two interaction sites. • A & A* occupy overlapping, identical volumes. • Enantioselectivity is dependant on the orientation of A & A* to the catalytic sites X or Y. • Attack from X, no selectivity; from Y potentially highly selective/specific.

  20. Four – Location Model • Isocitrate dehydrogenase: involved in the tricarboxylic acid cycle, converts (+)-(1R,2S)-isocitrate to 2-oxoglutarate & carbon dioxide. • In the presence of Mg2+ the enzyme binds (+)-(1R,2S)-stereoisomer, the substrate; in the absence of Mg2+ the (-)-(1S,2R)-enantiomer (not a substrate, weak inhibitor) binds.

  21. Concluded that four “interacting” sites are required for recognition’ or three sites with a directional requirement. Mesecar & Koshland (2000) Four – Location Model

  22. Chiral Recognition – Current View • Complex formation between the selector (receptor, enzyme) and selectand (drug, substrate) such that there is a diastereomeric relationship. • In the absence of other constraints, imposing a specific orientation of the selector to the selectand, a minimum of four “contact” points are required. • Thus the Easson-Stedman & Ogsten Models are specific cases of a Four Point Interaction. Bentley (2000)

  23. Chiral Pharmaceuticals the 1980s & 90s • During the “Golden Age” of drug discovery & development, the 1950s to the 1970s, stereochemistry was largely ignored resulting in approximately 25% of pharmaceuticals being marketed as racemates by the 1980s. • Advances in chemical technology associated with synthesis, analysis and preparative scale separation of chiral molecules resulted in a change in philosophy with respect to drugs. • Facilitated the Pharmacological evaluation of single stereoisomers; increasing concern with respect to safety issues; Regulatory interest.

  24. Drug Chirality: The 1980s Non chiral 6 Sold as single isomer Naturalsemisynthetic 475 461 Chiral 469 Sold as racemate Drugs 1675 8 Sold as single isomer Non chiral 720 58 Synthetic 1200 Chiral 480 Sold as racemate 422

  25. Pharmacodynamic Considerations • Stereoselectivity of drug action has been known for a number of years. • Many natural ligands are chiral, eg, transmitters, hormones, etc. • Additional Terminology: Eutomer : enantiomer with higher affinity/activity. Distomer : enantiomer with lower affinity/activity. Eudismic Ratio: Ratio of the Eutomer/Distomer affinities or activities. • Eudismic Ratios of 100 to 1000 fold are not uncommon.

  26. Eudismic Ratio • Terminology applies to a particular activity of a drug. • Dual action drug the Eutomer of one activity may be the Distomer for another. • Propranolol: S-enantiomer 40-100 fold more potent than the R- as a β-adrenoceptor antagonist; similar activity with respect to their membrane stabilising properties. • Eudismic Ratios may also vary with receptor subtypes. Noradrenaline: ER (R/S): α1, 107; α2, 480. α-Methylnoradrenaline: ER (1R,2S/1S,2R): α1, 60;α2, 550.

  27. Pharmacodynamic Complexity • Activity resides in a single enantiomer [(S)--Methyldopa]; • Both enantiomers have similar activity [Flecainide]; • Both enantiomers marketed with different indications [Propoxyphene]; • Enantiomers have opposite effects [Picenadol]; • One enantiomer antagonizes the side effects of the other [Indacrinone]; • Activity resides in one or both enantiomers, adverse effects predominantly associated with one [Ketamine]; • Racemate provides a superior therapeutic effect than either individual enantiomer [Dobutamine].

  28. Pharmacokinetics • Absorption - active transport. • Distribution - active/selective uptake, protein binding, selective tissues distribution. • Metabolism - numerous examples • Excretion - active secretion or reabsorption

  29. Enantiomeric Differences in Pharmacokinetic Profile

  30. Drug Stereochemistry Relatively little is known concerning the significance of • Route of administration, dose, formulation • Drug interactions • Age • Gender • Disease • Genetics

  31. Shift in plasma concentration effect • relationship following oral compared • to IV administration; • Drug less potent when given orally • compared to IV; • Due to stereoselective first pass • metabolism of the more active • S-enantiomer. • Eichelbaum et al. (1984). • Vogelgesang et al. (1984) Verapamil: Dose-response curve & route of administration

  32. More potent following oral • than IV administration; • Dose response curve shifts • to the left; • Due to steroselective first • pass metabolism of the less • active R-enantiomer. • Tucker & Lennard (1990). Propranolol: Potency and route of administration.

  33. Pharmacokinetics • As a result of stereoselectivity in drug disposition a pair of enantiomers rarely exist as 1:1 mixtures in biofluids. • Estimation of pharmacokinetic parameters, development of “Models” and/or concentration-effect relationships based on “total” drug are of limited value and potentially misleading. • Stereochemistry & “Sophisticated Nonsense”. Prof E.J.Ariens (1984)

  34. Body of Evidence “I’m not sure I get it,” Marino said, rubbing his eyes. “How can compounds be the same but different?” “Think of dextromethorphan and levomethorphan as identical twins,” I said. “They’re not the same people, so to speak, but they look the same – except one is right-handed and the other left-handed. One is benign, the other strong enough to kill. Does that help?” [Dr Kay Scarpetta] Patricia Cornwell, 1991

  35. Dextromethorphan Levomethorphan Patricia Cornwall Body of Evidence

  36. Use of Racemates • Isomeric ballast • “Clean” drugs • Polypharmacy

  37. FDA “The Agency is impressed by the possibility that the use of single enantiomers may be advantageous: (1) by permitting better patient control, simplifying dose-response relationships; (2) by reducing the extent of interpatient variation in drug response.”

  38. Potential Advantages of Single Isomer Products • Less complex and more selective pharmacological profile • Potential for an improved therapeutic index • Less complex pharmacokinetic profile • Reduced potential for complex drug interactions • Less complex relationships between plasma concentration and effect

  39. Racemates vs Enantiomers • No requirement from any regulatory authorities for marketing single isomers • Choice of stereoisomeric form must be justified on scientific grounds

  40. Handed Headlines (1) • S. Mason (1984) “The left hand of nature.” New Scientist 101:10-14. • D. Matterson (1991) “Through the chemical looking glass.” New Scientist 132:35-39. • I. Amato (1992) “Looking glass chemistry.” Science 256:964-966.

  41. Handed Headlines (2) • N. Moran “Drug firms sort their lefts from their rights.” Independent on Sunday (7/11/1993). • N. Hawkes “Lateral thinking.” The Times Magazine (5/6/1993). • T. Lister “Mirror images.” Guardian (11/1/1994).

  42. * = Stereogenic centre Thalidomide

  43. Thalidomide Enantiomers • Both are sedative in the mouse, only (S)-thalidomide is teratogenic. • Mouse is a poor model for teratogenicity. • Both are teratogenic in NZW rabbits. • Enantiomers undergo rapid racemization in vivo and in vitro. • In manfollowing administration of the R- and S-enantiomers ca 25% and 43% of the total AUC is due to the alternative stereoisomer.

  44. Strategies for the Synthesis & Preparation of Chiral Compounds • Use of optically pure starting materials: Carbohydrates, amino acids, alkaloids, steroids, other natural products. • Asymmetric Synthesis: Chiral catalysts. • Biological methods: Microorganisms and enzymes – “designer” enzymes (site directed mutagenesis). • Separations: Classical resolutions; Simulated Moving Bed (SMB); Supported Liquid Membrane.

  45. Value of Chiral Products & Approaches Growth rate 11.4% C&EN

  46. Chiral Switch • “Switch from a racemic to single enantiomer Active Pharmaceutical Ingredient is key to managing the life cycle, as well as improving the efficacy, of racemic drugs.” C&EN 2004

  47. Chiroscience UK • Dexketoprofen (Keral) 1996 • Levobupivacaine (Chirocaine) 1998 Sepracor USA • Levalbuterol (Xopenex, Xopenex HRA) • Eszopiclone (Lunesta, 2005) • Levocetirizine (Xyzal, Xusal) • Arformoterol (Brovana, 2007) • (S)-Amlodipine (USA Phase II clinical trials; India, marketed)

  48. Chiral Switch : Patents • One patent for a single isomer was refused because of a statement in a textbook that the biological effects of enantiomers can differ; • Another refused because the discovery of the effect was not an inventive step; but obvious from prior art; • Hence, patentability of single enantiomers is based on inventiveness not obvious from prior art. • “A patent on the racemate is a patent on the chemical formula without specifying stereochemistry.” C&EN 81 (2003) 56

  49. Enantiomeric Patents – Inhalational Anaesthetics • US Patents 5,114,714 & 5,114,715 • R-enantiomers of isoflurane and desflurane are “better” than the racemate; • S-enantiomers of isoflurane and desflurane are “better” than the racemate; • Essentially the only difference in the Patents are the R- and S- descriptors.

More Related