Chirality in therapeutics with enantiomer

Introduction
• Chiral chemistry was discovered by Louis Pasteur (1848)1
• Key role not only in the life of plants and animals but also in
pharmaceutical, agricultural and other chemical industries
• In pharmaceutical industries, 56% of the drugs currently in
use are chiral products and 88% of the last ones are marketed
as racemates
Chirality in therapeutics

Introduction
• All natural compounds are under single enantiomeric form
• Racemic drugs exhibit marked differences in biological
activities
• 2001 Nobel Prize in Chemistry : Dr. William S. Knowles and Pr.
K. Barry Sharpless and Pr. Ryori Nyori , for their development
of asymmetric synthesis of chiral molecules

Definitions & Nomenclature
• Chirality (stereoisomerism or
enantiomerism or dissymmetry)1
property of an object which is
non-superimposable with its mirror image
• A chiral molecule is a molecule having at least one
asymmetric carbon
• Enantiomers:2 The two non-superimposable mirror-image
forms of chiral molecules
• Chiral molecules exhibit optical activity, so enantiomers are
also sometimes called optical isomers
1

• The two enantiomers of chiral compounds may be classifed as levorotary (l-
isomer) or dextrorotary (d-isomer) depending on whether they rotate plane-
polarized light in a left (-) or right (+) -handed manner, respectively.
• Racemic mixture (racemate) An equimolar mixture (50/50) of the two
enantiomers of a chiral compound , with sign (±) or (d, l)

• Cahn-Ingold-Prelog (CIP) convention: Substituents of the higher
atomic number precede those with lower ones
• If the counting goes in a clockwise
direction, the configuration is
designated as R (rectus or right);
otherwise in a counter clockwise
direction, it is S (sinister or left)
• Each R- and S-enantiomers can rotate plane-polarized light,
therefore they can be designated as R(+) or R (-) and S (+) or S(-)

• Full description3 : Absolute descriptor + Relative descriptor +
generic name
e.g. S(-) Bupivacaine
• Eutomer refers to bioactive enantiomer or enantiomer having
higher pharmacological activity. Its opposite is called distomer
• Racemic/chiral switches are chiral drugs that have already
been approved as racemates and which have been redeveloped
as single enantiomer.
e.g. escitalopram, esomeprazole

Importance of chirality in therapeutics
• Each enantiomer by virtue of
its three dimensional structure
can interact with binding
sites of receptors and enzymes
differently 4
• Hence pharmacological differences could be pharmacokinetic or
pharmacodynamic which can affect therapeutic outcome

Pharmacokinetic implications5
• Absorption: L-methotrexate & esomeprazole is better
absorbed than D-methotrexate & omeprazole
• Distribution: S-warfarin & levocetirizine have lower volume of
distribution than their opposite enantiomers
• Metabolism: S-Warfarin is more potent and metabolized by
ring oxidation while R-Warfarin is less potent and metabolized
by side chain reduction, half life of S-Warfarin is 32 hours
while it is 54 hours for R-Warfarin

Pharmacodynamic implications4
• One enantiomer is ‘active’, while the other enantiomer is
“inactive”
 S-atenolol - beta blocking property resides in its S-form,
 levocetirizine – antihistaminic profile is associated with the R-enantiomer
(levo)
• One isomer is more potent than the other
 R-ondansetron
 S-pantoprazole
• Beneficial effects reside in one enantiomer, the other
enantiomer having antagonistic activity
 (S)-salbutamol, is indirectly involved in antagonizing the benefits of (R)-
salbutamol and may have proinflammatory effects

Pharmacodynamic implications
• Enantiomers have entirely different therapeutic possibilities
 R-fluoxetine is useful for depression while S-fluoxetine is envisaged for
migraine treatment
 S-propranolol has beta-blocking and membrane stabilizing property, its
counterpart, R-propranolol, has membrane stabilizing and spermicidal
properties and may be useful in hyperthyroidism
• Beneficial effects in one enantiomer whilst the other
enantiomer has adverse activity
 S-amlodipine is a calcium channel blocker (CCB) while R-amlodipine is
inactive as CCB and is thought to be responsible for pedal edema
observed with racemic amlodipine

Advantages of chiral drugs in therapeutics6
 Removal of unwanted pharmacodynamic side effects and
toxic effects
 Reducing metabolic/renal/ hepatic drug load compared to
racemic drug administration
 Easier assessment of physiology, disease, and drug
coadministration effects
 Reduce drug interactions

Advantages of chiral drugs in therapeutics
 Prevents enantiomer–enantiomer drug interactions if
present
 Avoids the probability for chiral inversion
 If the enantiomers are sufficiently different in
pharmacological effects, it may be possible to get a
patent on one or both
 Easier assessment of efficacy and toxicity through pk/pd
monitoring of the stereochemically pure active enantiomer
Pk-Pharmacokinetics, Pd- pharmacodynamics

Review of some important Unichiral drugs4
Sr.
no.
Unichiral
drug
Advantages over racemate
1 S-amlodipine  longer half-life of S-isomer
consistent pharmacokinetics due to less inter-subject
variability
 half the racemate dose, less metabolic load
 negligible pedal edema
2 S- metoprolol  can be administered at high doses without causing
beta-2 receptor mediated side effects
safer in poor metabolizers of CYP2D6
 avoids many drug-drug interactions

Review of some important Unichiral drugs
Sr.
no.
Unichiral drug Advantages over racemate
3 Esketamine  Two to three times more potent
 Eliminated more rapidly as a single enantiomer
 Incidence of psychotomimetic phenomena is
negligibly less
4 Eszopiclone  More active than R-zopiclone at the
benzodiazepine receptor complex
Shorter duration of action, which could minimize or
prevent residual hangover effects
5 Esomeprazole Could be metabolized by alternative pathways like
CYP3A4 and sulfotransferases
Clinically more effective than the racemate

FDA policy statement on development of chiral drugs3
• More difficult to obtain approval for racemates
• Approval could not be granted for drug containing more than
one isomer unless Pk/Pd properties of each could be
described and justified
• Additional isomers in a compound are no longer considered as
‘silent passengers’ but as potential contaminants (isomeric
ballast)
• Shortened approval process for the enantiomeric versions of
the approved drugs, with the promise of patent protection

Conclusion
• Trend in pharmaceutical industry towards development of
chiral drugs either de novo or by chiral switch
• Use of a single isomer must be seriously taken after long
clinical assessments between racemate and single enantiomer
actions
• Important to give more information about chiral drugs
especially racemic form to healthcare professionals in order to
help them for finding an optimal treatment and a right
therapeutic control

References
1. Nguyen LA, He H, Pham-Huy C. Chiral Drugs: An Overview. Int J Biomed
Sci. 2006 June; 2(2): 85–100.
2. Smith SW. Chiral Toxicology: It’s the Same Thing...Only Different. Toxicological
sciences. 2009 ; 110(1):4–30
3. Burke D, Henderson DJ. Chirality: a blueprint for the future. British journal of
anaesthesia. 2002; 88(4): 563-76
4. Chhabra N, Aseri ML and Padmanabhan D. A review of drug isomerism and its
significance. International Journal of Applied and Basic Medical Research. 2013
Jan-Jun; 3(1): 16–18.
5. Mohan SJ, Mohan EC, Reddy S, Manda S and Yamsani MR. Chiral interactions
and chiral inversions – new challenges to chiral scientists. International journal of
comprehensive pharmacy. 2011; 3 (01):1-9

Chirality in therapeutics with enantiomer

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