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CHIRALITY Stereochemical Categories

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CHIRALITY. Stereochemical Categories. ENANTIOMERS ... CHIRALITY: 1 asymmetric elements. More than one element of asymmetry? ... CHIRALITY AND DRUG ACTION ... – PowerPoint PPT presentation

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Title: CHIRALITY Stereochemical Categories


1
CHIRALITYStereochemical Categories
2
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
4
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
9
RECOGNIZING CHIRALITY
Chirality due to restricted rotation
(atropisomers)
R,S-gossypol
10
RECOGNIZING CHIRALITY
Chirality due to restricted rotation
(atropisomers)
R,S-methaqualone
11
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.
14
CHIRALITY two asymmetric centres
S
R
threo
erythro
R,S
S,R
S,S
R,R
Chloramphenicol
15
CHIRALITY two asymmetric centres
labetalol
S,R ?-receptor blockade
R,R ?-receptor blockade
dilevalol
16
CHIRALITY three or more asymmetric centres
penicillins
3S,5R,6R-penicillin G
erythromycin
262,144 isomers
17
CHIRALITY AND DRUG ACTION
Why do enantiomers have the potential for
exhibiting different pharmacodynamic and/or
pharmacokinetic properties?
18
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.
19
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
22
Pharmacological activity is, or appears to be,
due to one isomer
A.
?
Enantiomers have similar activities but
potencies differ.
R,S-verapamil
23
Pharmacological activity differs qualitatively
and quantitatively in each isomer
B.
?
Single enantiomer developed because antipode has
undesirable properties.
L-DOPA
dextropropoxyphene
24
Pharmacological activity differs qualitatively
and quantitatively in each isomer
B.
?
Single enantiomer developed because antipode has
undesirable properties.
S-timolol
25
Pharmacological activity differs qualitatively
and quantitatively in each isomer
B.
?
Racemate developed despite undesirable properties
of the antipode.
R,S-ketamine
R,S-disopyramide
26
Pharmacological activity differs qualitatively
and quantitatively in each isomer
B.
?
Racemate developed despite undesirable properties
of the antipode.
R,S-cyclophosphamide
27
Pharmacological activity differs qualitatively
and quantitatively in each isomer
B.
?
Combination product may have therapeutic advanta
ges.
rac-labetalol
28
Pharmacological activity differs qualitatively
and quantitatively in each isomer
B.
?
Combination product may have therapeutic advanta
ges.
R,S-indacrinone
29
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
30
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
31
GEOMETRIC ISOMERS
32
GEOMETRIC ISOMERS
33
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.
34
CONFORMATIONAL ISOMERS
Rotation about a bond
but
Infinite number of conformers
35
CONFORMATIONAL ISOMERS
there is a
  • preferred conformation

- steric repulsion
- electronic attraction
  • active conformation

- that which binds to receptor
36
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)

37
Conformation restriction by introduction of
double bond
chlorpromazine
chlorprothixene (E-isomer)
chlorprothixene (Z-isomer)
38
Conformation restriction by ring formation
39
Conformation restriction by ring formation
40
Conformation restriction by ring formation
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