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Master of Pharmacy Degree at King’s College London The College King’s is one of the two founding Colleges of the University of London: a major international university in the heart of London with approximately 14,000 undergraduate students and more than 5,000 postgraduates in nine Schools and five campuses. – School of Biomedical and Health Sciences – Dental Institute – School of Humanities – School of Law – School of Medicine – Florence Nightingale School of Nursing & Midwifery – School of Physical Sciences & Engineering – Institute of Psychiatry – School of Social Science & Public Policy School of Biomedical & Health Sciences School of Biomedical & Health Sciences The Department of Pharmacy • Master of Pharmacy • Master of Science Programmes Biopharmacy Pharmaceutical Technology Pharmaceutical Analysis & Quality Control • Master of Science / Diploma Programmes Primary Care & Community Pharmacy Supplementary Prescribing •Research Degrees in the Pharmaceutical Sciences & Pharmacy Practice School of Biomedical & Health Sciences Pharmaceutical Education & Training in the UK Master of Pharmacy (MPharm) Degree Four Years Pre-Registration Training : One Year Hospital Pharmacy Community Pharmacy Hospital or Community / Industry or Academic Pharmacy Professional Examination Registration: Member of the Royal Pharmaceutical Society of GB (RPSGB) School of Biomedical & Health Sciences MPharm 1: Principles of Pharmacy •Pharmacy orientation course (First three weeks) •Interprofessional Education (Throughout the Year) •Biochemical Basis of Therapeutics •Pharmacy Practice & Biopharmacy •Physical Pharmaceutics •Chemistry of Drugs School of Biomedical & Health Sciences MPharm 2 : Pharmacy &Therapeutics •Formulation & Analysis of Drugs •Nervous System •Respiratory & Musculoskeletal Systems •Cardiovascular & Renal Systems MPharm 3 : Pharmacy &Therapeutics •Medicines Discovery & Design •Gastrointestinal System & Skin •Infection & Pharmaceutical Microbiology •Endocrine System & Cancer •Pharmacy Law & Ethics School of Biomedical & Health Sciences MPharm 4 : Pharmacy into Practice Semester 1 : Research Project Semester 2 : Preparation for Practice Electives - Two from: • Chemical Mediators & Disease • Plants & Pharmacy • Drug Development from Natural Sources • Drug Delivery • Science of Dosage Form Design • Drug discovery & Design • Drug Metabolism • Drug Toxicity School of Biomedical & Health Sciences Department of Pharmacy and Overseas Study European Union Erasmus-Socrates Undergraduate students PhD students Post-doctoral staff Academic staff • Austria University of Vienna • France Joseph Fourier University, Grenoble • Germany Johann Wolfgang Goethe University, Frankfurt Philipps University, Marburg •Hungary Semmelweis University, Budapest • Italy University of Bologna University of Calabria University of Padova University of Parma • Poland Medical University of Łódź •Spain University of San Pablo CEU, Madrid University of Murcia School of Biomedical & Health Sciences Stereochemistry & Biological Activity Andrew J. Hutt Department of Pharmacy, King’s College London. Pharmaceutical & Medicinal Chemistry No drug was ever used because it had an: • Interesting synthetic pathway; • An unusual stability profile; • Required a particularly sophisticated analytical technique. Drugs are used because they “do” something! …….. and they “do” something as a result of their molecular structure, which determines: – Physicochemical properties; – Chemical / biochemical reactivity; – Shape; – STEREOCHEMISTRY. 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. Stereogenic centre A A D D B B C C Chiros – Greek Handed Sequence Rule Designation A A D D B B C C A>B>C>D S-enantiomer R-enantiomer Stereoisomers of Ibuprofen H H CH3 H3C (CH3)2CHCH2 CH2CH(CH3)2 COOH HOOC (-)-(R)-ibuprofen (+)-(S)-ibuprofen Stereogenic S & P centres CH3O N O O S : CH3 P N(CH2CH2Cl)2 N CH2 OCH3 O H NH N CH3 Esomperazole Cyclophosphamide Stereoisomers of Phenylpropanolamine H OH HO H CH3 CH3 H NH2 H2N H 1R,2R 1S,2S Norpseudoephedrine H OH HO H CH3 CH3 H2N H H NH2 1R,2S 1S,2R Norephedrine 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. Glyceraldehyde enantiomers CHO CHO H OH HO H CH2OH CH2OH D-(5.24) D- L-(5.24) L- CHO CHO H C OH HO C H CH2OH CH2OH D- L- D-(5.24) L-(5.24) Stereochemical Designations Spatial Arrangement Physical Properties – R/S – d,l – D/L – (+),(-) Optical Rotation (1) R S Propafenone Free base laevo dextro HCl salt dextro laevo Fenoprofen Free acid laevo dextro Sodium salt dextro laevo Optical Rotation (2) Chloramphenicol 1R,2R-absolute configuration Dextrorotatory in ethanol Laevorotatory in ethyl acetate Moxalactam Mixture of two epimeric diastereoisomers both of which are laevorotatory Nomenclature Dextro / Dex (+) Es (S) Dexamethasone Esomeprazole Dexamfetamine Escitalopram Dextromethorpan Eszopictone Dextropropoxyphene Levo / Lev (-) Ar (R) Levamisole Arformoterol Levobunolol Arflurbiprofen Levodopa Levonorgestrel D-Glucose CHO H OH H OH H O HO H HO H OH HO H OH OH H OH H CH2OH (2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanal (2R,3S,4R,5R)-aldohexose Amino Acids COOH COOH H2N H H2N H CH2OH CH2SH L-Serine L-Cysteine (S)-Serine (R)-Cysteine 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. Helical structures Left handed Right handed Differences Between Enantiomers: Odor R S Limonene Oranges Lemons Carvone Spearmint Caraway Differences Between Enantiomers: Taste D L Asparagine Sweet Tasteless Leucine Sweet Bitter Enantiomeric Discrimination Easson – Stedman Model (1933) Adrenaline & “Adrenergic Receptors” OH N H2CH 3 H N H 2C H 3 H HO HO HO HO HO ( R )- A d r e n ali n e (S )- A d re n a li n e H N H 2C H 3 H HO HO N - M e t h y l d o p a m i n e : A c h i r a l A n a lo g u e Pharmacology: Pharmacodynamics Stereoselectivity of drug action has been known for a number of years. Many natural ligands are chiral, eg, transmitters, hormones, etc. Pharmacodynamic Considerations Greatest differences between a pair of enantiomers occur at the level of receptor interactions. 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. Amosulalol Enantiomer Activity Receptor Tissue Eutomer pA2 Eudismic Adrenoceptor agonist (Enantiomer) Ratio Nonspecific β β1 Rat atrium 7.71 (-) 48 Selective α1 β2 Guinea pig 7.38 (-) 47 trachea α1 Rabbit aorta 8.31 (+) 14 α2 Rat vas 5.36 (+) 3 deferens H2NO2S OH H3C CHCH2NHCH2CH2 H3CO Stereoselectivity of Terfenadine H1-Antihistamine. Inhibition of mepyamine binding: R-, 6.4μM; S-, 7.5 μM. Ligand binding at H1-receptors Ki values: R-, 7.6; S-, 6.81. Blockade cardiac K+ channels: R-, 1.19 μM; S-, 1.16 μM. OH OH C (CH2)3 CH C(CH3)3 * Stereogenic centre located in a non critical region. Sertraline: Selective Serotonin Reuptake Inhibitor Inhibition of amine uptake (IC50; μM) CH 3 NH H Stereochemistry Serotonin Dopamine Noradrenaline Trans-(+)-1R,4S 0.033 0.033 0.011 Trans-(-)-1S,4R 0.45 0.23 0.050 H Cis-(+)-1S,4S 0.06 1.1 1.2 Cis-(-)-1R,4R 0.46 0.29 0.38 Cl Cl Formoterol NHCHO CH3 OH CH3O CH2CHNHCH2CH OH α β β Sample Eudismic Ratio Impurity Potency Ratio αR,βR/αS,βS (%) 1 14 ? αR,βR>αS,βR~αS,βS>αR,βS 2 50 1.5 αR,βR>αS,βR~αS,βS>αR,βS 3 850 0.1 αR,βR>αS,βR~αR,βS>αS,βS Pharmacodynamic Complexity: activity resides in a single enantiomer. (S)--Methyldopa, antihypertensive. (1R,2S)--methylnoradrenaline by dopa decarboxylase & dopamine β-hydroxylase. H H H OH HO NH2 HO NH2 CH3 COOH CH3 H HO HO Pharmacodynamic Complexity: Both enantiomers have similar activity. Promethazine – antihistamine; S enantiomers have similar pharmacological & toxicological N profiles. CH2CHN(CH3)2 CH3 Flecainide – antiarrhythmic CF3CH2O activity; effect on cardiac sodium channels similar; no significant CONHCH2 N pharmacokinetic differences. H OCH2CF3 Pharmacodynamic Complexity: Both enantiomers marketed with different therapeutic indications. Propoxyphene CH2–NMe2 CH2–NMe2 Me H H Me EtCOO C6H5 C6H5 OOCEt CH2–C6H5 CH2–C6H5 (+)-2R,3S (-)-2S,3R Analgesic Antitissive DARVON® NOVRAD Pharmacodynamic Complexity: Enantiomers have opposite effects at the same receptor. Picenadol Opioid analgesic – (+)-(3S,4R) enantiomer is agonist – (-)-(3R, 4S) enantiomer is antagonist – ()-(3RS, 4RS) partial agonist Pharmacodynamic Complexity: One enantiomer antagonises the side effects of the other. Indacrinone Loop diuretic, evaluated for treatment of hypertension and congestive heart failure Racemate administration results in elevated uric acid R-enantiomer: diuretic, t½ = 10 – 12 h S-enantiomer: uricosuric, t½ = 2 – 5 h Mixture S:R 4:1 isouricemic S:R 8:1 hypouricemic Pharmacodynamic Complexity: Required activity resides in one or both enantiomers, adverse effects predominantly associated with one enantiomer Ketamine, general anaesthetic with analgesic properties. S-enantiomer ca 3-fold greater affinity Cl for the NMDA receptor; 2-4 selectivity for μ- and κ-opioid receptors. NHCH3 Post-anaesthesia emergence reactions: O hallucinations, vivid dreams, agitation, mainly associated with the R- enantiomer. Chiral Switch, the S-enantiomer being available in Germany. Configuration & Activity H OH H OH ArOCH2 CH2NHR Ar CH2NHR S-Aryloxypropanolamine R-Arylethanolamine Pharmacology: Pharmacokinetics Absorption — active transport Distribution — active/selective uptake, protein binding Metabolism — numerous examples Excretion — active secretion or reabsorption Stereoselective drug absorption COOH COOH H2N H H2N H CH2 CH3 SH CH3 OH OH L-penicillamine L-dopa CH3 COOH NH2 N CHNH CONH H N CH2CH2COOH H2N N N L-methotrexate Stereoselectivity in plasma protein binding Acidic drugs Unbound (%) Ratio S-enantiomer R-enantiomer (S/R) Flurbiprofen 0.048 0.082 0.59 Ibuprofen 0.64 0.42 1.5 Indacrinone 0.3 0.9 0.33 Pentobarbitone 26.5 36.6 0.72 Phenprocoumon 0.72 1.07 0.67 Warfarin 0.9 1.2 0.75 Basic drugs Bupivacaine 4.5 6.6 0.68 Chloroquine 33.4 51.5 0.64 Disopyramide 22.2 34 0.64 Methadone 9.2 12.4 0.74 Mexiletine 28.3 19.8 1.4 Propafenone 2.5 3.9 0.64 Sotalol 62 65 0.95 Verapamil 11 6.4 1.7 Drug metabolism: Prochiral to chiral transformation OH pro-S [O] HN pro-R HN O O O O N N H H Phenytoin (S)-4-Hydroxyphenytoin Drug metabolism: Chiral to chiral OH CH2COCH3 OH CH2COCH3 CH CH CYP 2C9 O O HO O O Warfarin 7-Hydroxywarfarin Drug metabolism: Chiral to diastereoisomers H H H O N OH H HO OH O O COOH Cl N H C6H5 H H H O N R,D-Diastereoisomer OH Cl N H H C6H5 H O OH N HO OH Oxazepam O O COOH H H Cl N H H C6H5 S,D-Diastereoisomer Drug metabolism: Chiral Inversion of 2-Arylpropionic Acid NSAIDs H CH3 CH3 (CH3)2CHCH2 H (CH3)2CHCH2 COOH COOH (R)-Ibuprofen (S)-Ibuprofen Enantiomeric Differences in Pharmacokinetic Profile 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 Racemates vs Enantiomers (Cont’d) Configurational stability Preparation not technically feasible on a commercial scale Enantiomers have similar pharmacological and toxicological profiles One enantiomer is shown to be inactive and not provide an additional body of burden The use of a racemate produces a therapeutic effect superior to that of the individual enantiomers Penicillamine Originally introduced for the treatment of Wilson’s disease H NH2 Animal toxicity: weight loss, intermittent fits, death in rats; L >> D HS COOH Mutagenicity L > D Optic neuritis with racemate in man, drug withdrawn (USA) CH3 CH3 Dopa HO H HO CH2 C COOH NH2 decarboxylation L-Dopa Dopamine (natural neurotransmitter) Side effects: nausea, vomiting, anorexia, mental effects, involuntary movements, granulocytopenia Thalidomide O N * O NH O O * = Stereogenic centre 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 man following administration of the R- and S-enantiomers ca 25% and 43% of the total AUC is due to the alternative stereoisomer. Drug Chirality: The 1980s Non chiral Sold as single isomer Natural 6 semisynthetic 461 475 Chiral Sold as racemate 469 Drugs 8 1675 Non chiral Sold as single isomer 720 58 Synthetic 1200 Chiral Sold as racemate 480 422 New Chemical Entities Assessed by the UK Medicines Control Agency (MCA/MHRA) between 1996-2000 Non-chiral 2 Natural Single isomer 16 semisynthetic 19 Chiral 17 NCEs 95 Racemate 1 Non-chiral 31 Synthetic 76 Single isomer 30 Chiral 45 Shah & Branch, 2003. Racemate 15 Racemate – to – Enantiomer: Racemic or Chiral Switches Drug Name Class Approval Status Dexfenfluramine Anoretic Withdrawn Levofloxacin Antimicrobial Japan, UK, USA Dilevalol -blocker Development stopped Dexibuprofen NSAID Austria (1994), Switzerland, EU (2005) Dexketoprofen NSAID Spain, UK Levobupivacaine Local anesthetic UK (S)-Ketamine Anesthetic Germany Esomeprazole H+-pump inhibitor UK, USA (R)-Salbutamol 2-agonist USA (R)-Fluoxetine Antidepressant Development stopped Cisatracurium Neuromuscular blockade UK, USA Levocetirizine Antihistamine UK, (R,R)-Methylphenidate ADHD USA Escitalopram Antidepressant UK, USA (S)-Amlodipine Dihydropyridine India Eszopiclone Insomnia USA Arformoterol 2-agonist USA (April 2007) Armodafinil Antinarcoleptic USA (Approvable letter, April 2007) 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 CH3 CH3 H N N H H H H3CO (+) (-) OCH3 Patricia Cornwall Body of Evidence Further Reading A. Slovakova & A.J. Hutt (1999) Chiralne zluceniny a ich farmakologicke ucinky. Czech & Slovak Pharmacy, 48, 107-112. A.J. Hutt & J. Valentová (2003) The chiral switch: the development of single enantiomer drugs from racemates. Acta Facultatis Pharmaceuticae Universitatis Comenenianae, 50, 7-23. R. Čižmáriková, J. Valentová & A.J. Hutt (2004) Blokátory β-adrenergických receptorov – skupina chirálnych liečiv:enantioseparácie v skupine β-blokátorov. Czech & Slovak Pharmacy, 53, 9-17. J. Valentová & A.J. Hutt (2004) Chirálni záměna – “chiral switch”: čisté enantiomery léčiv místo racemických směsí. Czech & Slovak Pharmacy, 53, 285-293. R. Čižmáriková, J. Valentová, A.J. Hutt & S. Sedáková (2005) Blokátory β- adrenergických receptorov – skupina chirálnych liečiv stereoselektivna syntéza β- blokátorov. Czech & Slovak Pharmacy, 54, 201-206.
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