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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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