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 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.
(-)-(R)-ibuprofen (+)-(S)-ibuprofen Stereoisomers of Ibuprofen
Phenylpropanolamine: UK Confusion • Independent risk factor for hemorrhagic stroke in women1 • Withdrawn in the USA (FDA, Oct. 10, 2000) • (+)-norpseudoephedrine in European preparations;()-norephedrine in North America(Martindale 32nd; Pharm J, Nov. 11, 2000) •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.
Differences between stereoisomers are hard to detect normally, but become much more marked in a chiral environment
Chiral Biological Macromolecules • Proteins • Enzymes • Structural elements of membranes • Receptors • Carbohydrates • Nucleic acids • Chiral “building blocks” of L-amino acids and D-carbohydrates.
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.
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).
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)
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).
A D B C D' B' C ' Easson & Stedman (1933) Easson – Stedman ModelThree Point Interaction.
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.
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.
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.
Concluded that four “interacting” sites are required for recognition’ or three sites with a directional requirement. Mesecar & Koshland (2000) Four – Location Model
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)
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.
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
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.
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.
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].
Pharmacokinetics • Absorption - active transport. • Distribution - active/selective uptake, protein binding, selective tissues distribution. • Metabolism - numerous examples • Excretion - active secretion or reabsorption
Drug Stereochemistry Relatively little is known concerning the significance of • Route of administration, dose, formulation • Drug interactions • Age • Gender • Disease • Genetics
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
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.
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)
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
Dextromethorphan Levomethorphan Patricia Cornwall Body of Evidence
Use of Racemates • Isomeric ballast • “Clean” drugs • Polypharmacy
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.”
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
Racemates vs Enantiomers • No requirement from any regulatory authorities for marketing single isomers • Choice of stereoisomeric form must be justified on scientific grounds
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.
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).
* = Stereogenic centre Thalidomide
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.
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.
Value of Chiral Products & Approaches Growth rate 11.4% C&EN
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
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)
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
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.