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Chiral Drugs

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					           Chiral Drugs
Objectives: Drugs with chiral centers
represent a significant number of drugs on
the market. Upon completion of this lecture,
the student will be aware of advantages of
chiral drugs as therapeutic agents, including
the importance of chirality in drug specificity,
and approaches used for the production of
chiral drugs.
                                                                          H
                                                           CONH2
                                               O                    OH
                                                               H                   H
                                        N                      N          N


$159 billion dollar
                                                   N
                                                   H
                                                           O                  CONHtBu



market in 2002
                                        Saquinavir (Roche, RO31-8959)
Phase I clinical trial: ~60 Kg
Phase II and III trials: ~600 Kg
Market drug: tons!
                                                       S
                                                                    O    NHtBu
                                                   O
                                   HO
                                                       N            N
                                                       H
                                                               OH




                                            Viracept (Agouron AG1343)
Chiral blockbuster drugs




     C&E News, June 14, 2004, p. 47
                Racemic switches

Economic considerations
  i) overcome patent protection
  ii) circument generics
  iii) Sepracor

Biological considerations
  i) “active” isomer
  ii) “non-active” isomer: side effects
  iii) different pharmacokinetic/metabolic profiles
Racemic switches

 (S)-(+)-Ibuprofen
    Ketoprofen
     Albuterol
      Allegra
  Desloratadine
   (R)-fluoxetine
    Stereochemistry definitions
                                    O                  O

                                        OH

enantiomers
diastereomers                   OH                 OH      OH
                                A       A          A       A
epimers
geometric isomers
                    Example of epimers and how interactions with
                    hydrogen bond acceptors, A, on a hypothetical
                    receptor occur.
            Easson-Stedman Principle

                   H                H                   H


                   C                C                   C

            A           B       A           B   A               B
                                                        H
                   G                G

                                                      
                                                       


               A            B                       C


A) Incorrect enantiomer B) correct enantiomer and C) achiral
   analog interacting with three points on a hypothetical
   receptor.
Binding of A) l-epinephrine, B) d-epinephrine and
    C) dopamine to a hypothetical receptor
                     CH2        H
           R
                NH2+                         OH


               (-)         OH
                                            A              A
                           A            OH
                                        A

                                                                      OH
                                                  R         CH2
                                                       NH2+                         OH

                                                      (-)         H
                                                                                   A
                                        B                         A            OH
                                                                               A


                               H
           R         CH2
                NH2+                         OH


               (-)
                           H
                                            A          C
                       A                OH
                                        A
Binding of enantiomers to the muscarinic
    acetylcholine receptor: agonists
                                                               CH3 (+)
                                   O                                   CH3
                                                   CH2         N
                                                                       CH3
                          CH3 C            O             CH2

                                       EC50 = 0.1 uM

                                                                               CH3         CH3 (+)
                 H             CH3 (+)                                               H
                         CH3
                                                                       O                       CH3
        O                              CH3                                       C         N
                     C         N                                                               CH3
                                       CH3                     CH3 C         O       CH2
     CH3 C   O           CH2

             EC50 = 0.16 uM                                                  EC50 =79 uM

                                                                   CH3
                                       O                                 CH3
                                                    CH2            C
                                                                         CH3
                           CH3 C               O          CH2

                                               EC50 =100 uM
Binding of enantiomers to the muscarinic
   acetylcholine receptor: antagonists
                                                                  CH3 (+)

                                 OH        O                            CH3
                                                      CH2         N
                                                                        CH3
                                      C C       O           CH2
                        Phenyl
                           Phenyl

                                               IC50 = 2.5 nM


                                        CH3 (+)                                                 CH3 (+)
                       CH3        H                                               H       CH3
          OH     O                              CH3               OH        O                       CH3
                             C          N                                             C         N
                                                CH3                                                 CH3
                C C    O          CH2                                   C C      O        CH2
     Phenyl                                               Phenyl
       Phenyl                                               Phenyl

                      IC50 = 10 nM                                              IC50 = 7.9 nM
                                                                        CH3

                                      OH        O                               CH3
                                                            CH2         C
                                                                                CH3
                                            C C       O           CH2
                             Phenyl
                                 Phenyl

                                                    IC50 = 50 nM
Production of enantiomeric
          drugs
 Phase I: approximately 60 Kg of drug required
 Phase II and III: approximately 600 Kg of drug
 required
 Production: Multiton quantities

 Resolution
 a) Diastereomeric or chemical resolution
 b) Enzymatic or biological resolution.
Production of enantiomeric drugs
                enzymatic resolution


             OC2H5                                 OC2H5

                      O                                      OH
                 C        C2H5                         C

C2H5O2C          O                     C2H5O2C         O




          Example of chemical reaction catalyzed by lipase
                         Transaminases

                                        O         (S)-transaminase               NH2
Chemical reaction catalyzed by
  transaminase to produce an
                                            NH2                      O
  enantiomeric amine
                                  H3C       C CH3             H3C C CH3
                                            H




                                                                           NH2

Chemical reaction catalyzed
                                 NH2
by transaminase to degrade
an unwanted enantiomeric                          (R)-transaminase
                                                                           +
amine                                                                      O
                                        CH3CH2CHO           CH3CH2CH2NH2
                            Microorganisms
Conversion of aromatics to chiral diols by bacteria

    X                 X
                            OH                OH


                            OH                OH

        X = Cl, Br, O, CN
      Chiral chromatography


i) HPLC column packed with chiral polymer


ii) High yields, inexpensive
                    Asymmetric synthesis

enantiomeric reagents                                                      CH2


                                                                                 CO2H

chiral catalyst
                                                               H2
resolve enantiomers                                            catalyst
                                                                           CH3


                                           P(C6H5)2                              CO2H
                                       O
                                            RuCl2
                                       O
Example of a chiral chemical               P(C6H5)2
                                                              oxidation

catalyst (on left) and the catalyzed                   O                   CH3

reaction (in the presence of H2) and
                                                                                 CO2H
the subsequent oxidation step

                                                      (S)-(+)-Ketoprofen