STEREOCHEMISTRY
CONSIDERATIONS
Most natural organic products, the
essential products of life, are
asymmetric ... This established
perhaps the only well marked line of
demarcation that can at present be
drawn between the chemistry of dead
matter and the chemistry of living
matter.
Louis Pasteur, circa. 1848
1
Therapeutic
Armamentarium
Non-optically active Optically active
Drugs (40%) drugs (60%)
2
I.
NOMENCLATURE
CHIRAL CARBON: A carbon atom
which has 4 different ligands
attached and is thereby
asymmetric.
Result is:
nonsuperimposable mirror images
rotate polarized light
3
CO 2 CO 2
H
H
H3C CH 3
NH 2 H2N
L-(+) alanine D-(-) alanine
4
Dextrarotatory – d or (+)
Levorotatory- l (-)
erms for non-superimposable images:
ptical isomers
ptical antipodes
nantiomers
identical physical/chemical propert
5
rotation = configuration
R – rectus or
D
S – sinister
hermodynamic equilibrium – or
50:50 mixtu
L mixture: d, l or +,-
Racemic
Ex: d,l-propranolol
6
Epimerization – formation
of
• possess> 1 chiral center
diastereomers
• Inversion of 1 chiral
center produces a cmpd
that is not a mirror
image
• May have different
chemical and physical 7
H CH=CH2 H
CH=CH2
N
N H
H H3CO
H3CO
H OH
H OH
N
N
Quinidine [8R, 9S] Epiquinidine [8R, 9R]
H H CH=CH2
CH=CH2
N
H N
H3CO H
H3CO
HO H
HO H
N
N
8
Quinine [8S, 9R] Epiquinine [8S, 9S]
PREFIXES USED TO DENOTE
CHIRAL PROPERTIES
PREFIX PROPERTY
d-/l- Rightward (dextro), clockwise/Leftward
(leuvlo), counterclockwise, optical rotation.
Used interchangably with (+)/(-)
D-/L- Rightward/leftward arrangement of
substituents about chiral center (archaic,
used for amino acids & carbohydrates)
R-/S- Rightward (rectus)/leftward (sinister) arrange-
ment of substituents about chiral center
(modern, used for drugs)
e.g., R-(-)- levorotatory, but with absolute configuration R
9
II. PHARMACODYNAMIC
SIGNIFICANCE OF
STEREOISOMERS
CH3 CH3
O O
H3C CH2 H2C CH3
d-carvone l-carvone
(CARAWAY) (SPEARMINT) 10
A A D
D D A
B B B
C C C
D' D'
B' B'
C' C'
Enantiomeric interactions with a chiral biological macromolecule
(Easson-Stedman model). The enantiomer on the left is involved
with 3 simultaneous bonding interactions with complementary
functionalities on the receptor, whereas that on the right interacts at
2 sites only. Alternative receptor orientations of the enantiomer on
the right are possible, but only 2 complementary interactions may
take place at any time. From Hutt AJ, Tan SC (1996) Drugs 52:S1-S12.
11
O O
NHCH3 NHCH3
Cl Cl
S-(+)-Ketamine R-(-)-Ketamine
2-4 times more potent than Causes spontaneous motor
R-(-)-ketamine in activity and post-emergent
anaesthesia distress
12
Reproduced from: Rowland M, Tozer TN. Clinical Pharmacokinetics – Concepts and
Applications, 3rd edition, 1995, p. 341.
13
Relative Pharmacodynamic Potency of
Selected Enantiomers
Compound Relative Activity Biological Response
terbutaline - > + (3000:1) trachea relaxation
propranolol S > R (100:1) block tachycardia
pindolol - > + (200:1) inhibit tachycardia
methadone - > + (3:1) respiratory depression
ketamine S > R (4:1) anesthesia
tocainide R > S (3:1) antiarrhythmic
flecainide +=- antiarrhythmic
propafenone +=- antiarrhythmic
disopyramide S>R antiarrhythmic
disopyramide S>R anticholinergic
warfarin S > R (8:1) anticoagulant
verapamil - > + (5-18:1) block AV conduction
Data from: Jamali F, et al. J Pharm Sci 78:695, 1989. 14
• Enantiomers have identical
efficacy and toxicity
• Enantiomers may have the same
therapeutic and toxic effects, but
differ in magnitude
• One enantiomer may possess
virtually all the pharmacological
activity while the other is
essentially biologically inactive
• Both enantiomers may be
pharmacologically active but
have qualitatively different
therapeutic and toxic effects
15
H H
H 3C H 3C
CH3 COOH CH3 COOH
H 3C H 3C
S-Ibuprofen R-Ibuprofen
Inhibits platelet thromboxane Racemizes to the S-form and does
production twice as effectively as does not cause G.I. lesions
the racemate
16
Enzymatic scheme for inversion of R-ibuprofen to S-ibuprofen.
acyl CoA synthetase hydrolase
R-IBU R-IBU-CoA R-IBU
CoA ATP, Mg++
racemase
S-IBU S-IBU-CoA S-IBU
hydrolase
17
• Mixed agonist activity from chiral mixtures
RR
8 SS
Potency (pA2)
RS
7 SR
5
alpha 1 beta 1 beta 2
Relationship between steric structure and the biological activity of
labetalol. From: Ariens EJ. Eur J Clin Pharmacol 26:663, 1984.
18
III. STEROSELECTIVITY OF
PHARMACOKINETIC
PROCESSES
A. ABSORPTION
Frel D-methotrexate/L-methotrexate = 0.025
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III. STEROSELECTIVITY OF
PHARMACOKINETIC
PROCESSES
[Link]
[Link]
Drug Free Fraction Ratio
(+/-)
+ -
disopyramide 0.27 0.39 0.7
ibuprofen 0.006 0.0039 1.5
mexilitine 0.283 0.198 1.4
methadone 0.092 0.124 0.7
propoxyphene 0.018 0.018 1.0
propranolol 0.203 0.176 1.2
tocainide 0.17 0.14 1.2
verapamil 0.064 0.11 0.620
warfarin 0.012 0.009 1.3
C. METABOLISM
Drug Clearance Form (+) (-) Ratio
disopyramide Clu,[Link] isomer 0.23 0.18 1.28
propranolol CLiv racemate 1.21 1.03 1.17
CLu,iv racemate ~6.0 ~5.9 1.02
CLo racemate 2.78 1.96 1.42
CLu,o racemate 13.7 11.1 1.23
verapamil CLiv isomer 0.80 1.40 1.75
CLu,iv isomer 5.96 5.85 1.02
CLo racemate 1.72 7.46 4.33
warfarin CLo racemate 0.234 0.333 1.42
CLu,o racemate ~21.9 ~37.0 1.69
Data from: Tucker GT ,Lennard MS. Pharmacol Ther 45:309-329, 1990.
21
Effect of route of administration on plasma-concentration-response
relationships based upon measurement of unresolved verapamil and
propranolol. The shifts in the data following oral and i.v.
administration may be explained by stereoselective first-pass
metabolism. (Data from Eichelbaum et al. (1984); Vogelgesang et al.
(1984); Coltart and Shand (1970).) from: Tucker GT, Lennard MS.
Pharmacol Ther 45:309-329, 1990.
22
From: Olbe et al, Nat Rev Drug Discovery 2:132, 2003 23
CYP isoforms do different jobs on each enantiomer:
O O
O O O
P O P
CYP2B6 P
NHCH2CH2Cl H2N N
NH NHCH2CH2Cl
N
ClH2CH2C
S-3-Dechloroethylifosfamide CYP3A4 CH2CH2Cl
R-Ifosfamide S-2-Dechloroethylifosfamide
O
O CYP2B6
P O
O
NH2 O P
N O
P CYP3A4 ClH2CH2CHN
CH2CH2Cl HN
ClH2CH2CHN N
R-2-Dechloroethylifosfamide R-3-Dechloroethylifosfamide
ClH2CH2C
+ +
S-Ifosfamide
ClCH2CHO ClCH2CHO
Chloroacetaldehyde Chloroacetaldehyde
(Neurotoxic) (Neurotoxic)
24
D. EXCRETION
Drug Clearance Form (+) (-) Ratio
chloroquine CLR,u racemate 824 519 1.6
Disopyramide CLR,u isomer 338 182 1.8
mexilitine CLR racemate 0.5 0.5 1.0
pindolol CLR,u racemate 453 534 1.2
terbutaline CLR isomer 2.7 1.5 1.8
tocainide CLR isomer 55 55 1.0
25
26
IV. IMPACT OF STEREOSELECTIVITY ON
PHARMACO-KINETIC AND PHARMACODYNAMIC
PARAMETER ESTIMATES WHEN USING NON-
SPECIFIC ANALYTICAL METHODS
27
(+) (-)
0 2 4 6 8 10
(+)/(-)?
0 2 4 6 8 10
(-)
(+)
28
0 2 4 6 8 10
log C
[RS]
[S]
[R]
Time
Plasma concentration-time profile for a drug which exhibits
stereoselective disposition. Individual isomers exhibit
monoexponential decline. However, using a non-stereospecific
assay results in apparent biexponential disposition. 29
[RS]
[S]
log C
[R]
Time
Plasma concentrations of the same hypothetical drug during
multiple dosing. Note that the drug becomes increasingly enriched
in the S form. Obviously, this will lead to a large degree of
variability in the concentration-effect relationship, depending upon
when determinations are made. 30
