effect of chirality on therapeuticaly active agents

1. Case study of
stereochemistry
and drug design
PREPARED BY: ARZOO DHARASANDIYA GUIDED BY: UTTAM MORE
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY
SHREE DHANVANTRY PHARMACY COLLEGE

2. Recemic switches
• A "racemic switch" is the redevelopment in single-enantiomer form of a drug that
was first approved as a racemate.
• Sometimes, the pharmaceutical activity is in only one enantiomer and the other
is inactive, or the "other" enantiomer has a different kind of activity from the first.
• Esmoprazole is the S-enantiomer of omeprazole.it is the most successful
racemic switches launched.

3. Racemic switches
Generelly the (±)-ibuprofen racemate is used ,but only (S)-
enantiomer has the anti-inflammatory action.

4. propranolol

5. Difference between (+)prorpranolol and (-
)propranolol
• 1. The optical isomers of propranolol have been compared for their β-blocking
and antiarrhythmic activities.
• 2. the protein binding of propranolol to AGP is stereoselective for the S-
enantiomer, whereas binding to HSA favors (R)-propranolol.
• In whole plasma the binding to AGP is dominant so that the free fraction of the
R-enantiomer is greater than that of (S)-propranolol.

6. Stereoselective vascular effects of the (R)- and
(S)-enantiomers of propranolol and atenolol.
• The drugs are believed to be contraindicated when peripheral vascular disease
exists, presumably due to unopposed alpha-adrenergic vasoconstriction.
• However, little is known about direct vascular effects of beta-blockers or of
stereoselective effects on peripheral arteries.
• Therefore, we investigated the effects on forearm blood flow (FBF) of brachial
artery infusions of the (R)- and (S)- enantiomers of propranolol and their
inhibitory effects on isoprenaline (Iso)-induced vasodilatation by forearm venous
occlusion plethysmography in 12 healthy subjects.
• Only (R)-propranolol caused an increase in FBF (+21%, p < 0.05), whereas (S)-
propranolol had no direct effect on peripheral arteries.
• Our results indicate that the optically pure (R)- and (S)-enantiomers of
propranolol and atenolol do not exert direct vasoconstrictive effects.

7. thalidomide
The body racemises
each enantiomer, so
even pure S is
dangerous as it
converts to R in the
body.

8. • Thalidomide exists in two mirror-image forms: it is a racemic mixture of (R)- and
(S)-enantiomers.
• The (R)-enantiomer, shown in the figure, has sedative effects, whereas the (S)-
isomer is teratogenic.
• Under biological conditions, the isomers interconvert, so separating the isomers
before use is ineffective.
• he direct target of thalidomide had been a long-standing question. We identified
cereblon as a primary direct target protein for thalidomide teratogenicity using
new affinity bead technology in 2010.

9. • Thalidomide, sold under the brand name Immunoprin, among others, is
an immunomodulatory drug and the prototype of thethalidomide class of drugs.
Today, thalidomide is used mainly as a treatment of certain cancers (multiple
myeloma) and of a complication of leprosy.

10. naproxen

11. STEREOSELECTIVE SYNTHESIS OF
NAPROXEN

12. naproxen
• (S)-(+)-naproxen is used to treat arthritis pain, but (R)-(–)-naproxen causes liver
poisoning with no analgesic effect.
• Mechanism of liver damage
• The mechanism of hepatotoxicity from naproxen is not known, but it is
metabolized by the cytochrome P450 system and idiosyncratic injury may be
due to a toxic metabolite. Cross sensitivity to hepatic injury with fenoprofen
suggests that the propionic acid may be responsible for the injury.

13. DIETHYLSTILBESTEROL
Diethylstilbesterol is used in the prostate cancer. Out of the two forms trans form is 14
times more potent than the cis form.

14. ETHAMBUTOL
the (S,S)-(+)-enantiomer is
used to treat tuberculosis,
the (R,R)-(–)-ethambutol
causes blindness.

15. QUININE & quinidine
Quinine is a medication used to
treat malaria and babesiosis.
Quinidine is
a pharmaceutical agent that acts as
a class I antiarrhythmic agent (Ia) in
the heart.[1] It is
a stereoisomer of quinine

16. Amphetamine & dextroamphetamine
amphetamine dextroamphetamine

17. • When it comes to contraindications,
the amphetamine is noted to
increase cardiac output and blood
pressure.
• Thus, this drug is often prohibited
for use by people who are suffering
from heart diseases and
hypertension.
• There are some indications that
people who take the drugs together
with MAOI or monoamine oxidase
inhibitors can lead to life threatening
situations.
• On the other hand, the
dextroamphetamine is noted to have
contraindications of advanced
arteriosclerosis, symptomatic
cardiovascular diseases,
hypersensitivity and glaucoma.
• It is also noted that persons who
have taken MAOI drugs with the
dextroamphetamine can have
effects of hypertensive crises.

19. • This drug is available as a mixture of both (S)-(–)-ketamine, also known
as esketamine, and (R)-(–)-ketamine, also known as arketamine.
• Pure esketamine is also available.
• The two have different dissociative and hallucinogenic properties, with
esketamine being more potent in isolation as a dissociative.
• The two enantiomers have inverse effects on the rate of glucose metabolism in
the frontal cortex.

20. Biological Discrimination

21. OTHER EXAMPLES
CH3
HCCH2
CH3
CH3
H C CH2
H3C
S limonene (lemons) R limonene (oranges)
The more common R-
isomer possesses a
strong smell of
oranges.
The other mirror-image
isomer (or enantiomer), S-
limonene, has a pine or
turpentine-like odour.

22. O
CH3
H C CH2
H3C
O
CH3
HCH2C
CH3
S caravone
Caraway
seed
R caravan
spearment
Caraway Seed has a warm, pungent, slightly
bitter flavour with aniseed overtones.
Sweet spearmint, fresh herbalcaraway, fresh herbal

23. references
• i. Text book of organic chemistry – K.S. Mukherjee
• ii. Advanced Organic Chemistry – Jerry March
• iii. Organic Chemistry – Morrison and Boyd
• iv. STEREOCHEMISTRY BY FOYE