CHIRALITY Stereochemical Categories

1
CHIRALITYStereochemical Categories
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ENANTIOMERS
Enantiomers have identical physical and chemical
properties.
EXCEPT
Ability to rotate the plane of polarized light
and
Rate of reaction and interaction with other
chiral compounds and environments
3
DESCRIPTORS IN STEREOCHEMISTRY
, -
d, l
dextro, levo
Rotation
Configuration
R, S
D, L
No relation between rotation and configuration.
e.g. S-()-naproxen
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RECOGNIZING CHIRALITY
Compounds with chiral carbon
S-()-naproxen
S-(-)-timolol
5
RECOGNIZING CHIRALITY
Compounds with chiral nitrogen
6
RECOGNIZING CHIRALITY
Compounds with chiral phosphorus
R,S-cyclophosphamide
7
RECOGNIZING CHIRALITY
Compounds with chiral sulfur
R,S-sulindac
8
RECOGNIZING CHIRALITY
Metallic coordination complexes
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RECOGNIZING CHIRALITY
Chirality due to restricted rotation
(atropisomers)
R,S-gossypol
10
RECOGNIZING CHIRALITY
Chirality due to restricted rotation
(atropisomers)
R,S-methaqualone
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RECOGNIZING CHIRALITY
Chirality due to helical or semihelical shapes.
benzodiazepines
12
RECOGNIZING CHIRALITY
Chirality due to nonplanarity.
telenzepine
13
CHIRALITY gt1 asymmetric elements
More than one element of asymmetry?
The maximum number of configurational isomers in
a compound with n asymmetric elements is 2n.
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CHIRALITY two asymmetric centres
S
R
threo
erythro
R,S
S,R
S,S
R,R
Chloramphenicol
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CHIRALITY two asymmetric centres
labetalol
S,R ?-receptor blockade
R,R ?-receptor blockade
dilevalol
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CHIRALITY three or more asymmetric centres
penicillins
3S,5R,6R-penicillin G
erythromycin
262,144 isomers
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CHIRALITY AND DRUG ACTION
Why do enantiomers have the potential for
exhibiting different pharmacodynamic and/or
pharmacokinetic properties?
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CHIRALITY AND DRUG DEVELOPMENT
A.
Pharmacological activity is, or appears to be,
due to one isomer.
B.
Pharmacological activity differs qualitatively
and quantitatively in each isomer.
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Pharmacological activity is, or appears to be,
due to one isomer
A.
?
Only one isomer is active, the other is
inactive.
R,S-?-methyldopa
20
Pharmacological activity is, or appears to be,
due to one isomer
A.
?
Both enantiomers have similar activity and
potency.
R,S-flecainide
21
Pharmacological activity is, or appears to be,
due to one isomer
A.
?
Enantiomers have similar activities but
potencies differ.
R,S-propranolol
R,S-warfarin
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Pharmacological activity is, or appears to be,
due to one isomer
A.
?
Enantiomers have similar activities but
potencies differ.
R,S-verapamil
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Pharmacological activity differs qualitatively
and quantitatively in each isomer
B.
?
Single enantiomer developed because antipode has
undesirable properties.
L-DOPA
dextropropoxyphene
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Pharmacological activity differs qualitatively
and quantitatively in each isomer
B.
?
Single enantiomer developed because antipode has
undesirable properties.
S-timolol
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Pharmacological activity differs qualitatively
and quantitatively in each isomer
B.
?
Racemate developed despite undesirable properties
of the antipode.
R,S-ketamine
R,S-disopyramide
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Pharmacological activity differs qualitatively
and quantitatively in each isomer
B.
?
Racemate developed despite undesirable properties
of the antipode.
R,S-cyclophosphamide
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Pharmacological activity differs qualitatively
and quantitatively in each isomer
B.
?
Combination product may have therapeutic advanta
ges.
rac-labetalol
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Pharmacological activity differs qualitatively
and quantitatively in each isomer
B.
?
Combination product may have therapeutic advanta
ges.
R,S-indacrinone
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ENANTIOSELECTIVE PHARMACOKINETICS
Enantioselectivity in pharmacodynamics can result
not only from qualitative and quantitative differe
nces but also from differences in the
pharmacokinetics of the enantiomers.
Absorption Distribution Protein
binding Metabolism Excretion Drug
interactions Polymorphism
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GEOMETRIC ISOMERS
Type of diastereoisomers that occur as a result
of restricted rotation about a bond.

• physical properties different

• differences in pharmacodynamics may be due to
  differences in

- physical properties
- spatial differences
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GEOMETRIC ISOMERS
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GEOMETRIC ISOMERS
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CONFORMATIONAL ISOMERS
Non-identical spatial arrangement of atoms in a
molecule resulting from rotation about one or
more single bonds.
Rotational (or conformational) isomers of butane.
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CONFORMATIONAL ISOMERS
Rotation about a bond
but
Infinite number of conformers
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CONFORMATIONAL ISOMERS
there is a

• preferred conformation

- steric repulsion
- electronic attraction

• active conformation

- that which binds to receptor
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CONFORMATIONAL ISOMERS
Benefits of conformational restriction

• locks in desired conformation

• improves understanding of drug-receptor
  interaction

• more effective drugs

Conformation restriction introduced by means of

• double bond

• ring formation (closure)

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Conformation restriction by introduction of
double bond
chlorpromazine
chlorprothixene (E-isomer)
chlorprothixene (Z-isomer)
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Conformation restriction by ring formation
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Conformation restriction by ring formation
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Conformation restriction by ring formation