chiral drugs
TRANSCRIPT
GOOD MORNING
After all! The aim of Pharmacology is to provide medicines which have increased efficacy and enhanced safety!
Nanotechnology, Biotechnology and Chiral technology ………
Aim of medication
CHIRAL DRUGSCHIRAL DRUGS
Dr Shahid SaacheDept. of Pharmacology
BJ GMC, Pune
Guide: Dr Sujeet Divhare
Isomer
Compounds with same molecular formula, but different structural formula or different spatial arrangement
ClCl
and
1-chloropropane 2-chloropropane
Stereoisomers
Identical molecular formula, atom to atom linkages and bonding distances, but differ in their 3-dimensional arrangement
Diastereomers
Stereoisomers which are non-superimposable, non-mirror image
D-Threose D-Erythrose
EnantiomersSteroisomers which are non-superimposable mirror images
(S)OH
O
O O
(R)
O
HO
S(+) ketoprofen R(-) ketoprofen
Chiral object
Chiral object is
not
super-imposable
on its mirror
image.
Chiral object
Chiral terms(+), d Dextrorotatory(--), l, Levorotary.(R)- Rectus(S)- SinisterMeso - optically inactive isomerDistomer- Enantiomers with least
pharmacological effect.Eutomer- Enantiomers with higher
pharmacological effect
History
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Hauy in 1809 Postulated isomerism between molecular shape and crystal shape
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Chirality of a molecule was first reported in 1815 by a French Physician Jean Baptist Biot.In 1835 discovered the rotation of the polarization of light in sugar solution.
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The first chiral separation, which laid the foundation for stereochemistry, was reported in 1848 by Louis PasteurIn 1858 Louis Pasteur discovered that the two isomers of tartaric acid polarized light differently.
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Dutch physical chemist Jacobus Hendricus van’t Hoff and the French chemist Achille Le Bel independently theorized that the molecular basis of chirality that was first observed by Pasteur was an asymmetric carbon.
In 1893 Lord Kelvin gave a definition for chirality that has stood the test of time.
Cahn Ingold and Vladimir Prelog: Nomenclature
Why Chirality??
Thalidomide tragedy
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Nomenclature of IsomersAbsolute descriptors (R and S)An order of priority is attached to substituent ligands attached to the central chiral atom. If the sequence of the ligands in terms of size (largest to smallest) produces a clockwise progression, the arrangement is termed ‘R’- from the Latin rectus (right); an anti clockwise order is termed ‘S’- from the Latin sinister (left)
R S
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Relative descriptors
Clockwise optical light rotation: (+)
Anticlockwise optical light rotation: (-)
+
-
Nomenclature of Isomers
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R/S & +/- are mutually exclusive
S may be (+) or (–) for different compounds e.g. S(-) Amlodipine S(+) Zopiclone
Similarly, R may be (+) or (–) for different compounds
e.g. R(+) Amlodipine R(-) Zopiclone
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R/S & +/- are mutually exclusive
But, for a given compound, if S is (-), R will be (+) and vice versa
e.g. S(-) Amlodipine R(+) AmlodipineS(+) Zopiclone R(-) Zopiclone
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Optically Pure Compound
A collection containing
only one enantiomeric
form of a chiral molecule
is called: Enantiopure,
Enantiomerically pure, or
Optically pure compound.
A collection containing
equal amounts of the two
enantiomeric forms of a
chiral molecule is called a
Racemic Mixture or
Racemate.
Racemate
• Arthur R. Cushny: Believed that the “receptor” was chiral & combined with the enantiomers of the drug to produce diastereoisomeric drug – receptor complexes.
• Left handed molecules fit only the left handed receptors and same is true for right handed molecules.
Chiral receptor
(Pharmacodynamics- Drug receptor interaction; adverse drug reactions. Pharmacology and Pharmacotherapeutics. Satoskar RS,Rege NN, Bhandarkar SD,edition 24 ;2015:2-49).
Illustration of two isomeric forms of a chiral molecule and how their interaction with a biological target, a receptor surface or protein, is specific for the arrangement of the
substituent groups around the chiral carbon.
• Enzymes are capable of distinguishing between stereoisomers
Chirality
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Pharmacokinetic implications
Absorption
Active transport processes are stereoselective. e.g.,
Bioavailability of (R)-verapamil is ˃ double that of (S)-
verapamil due to reduced hepatic first-pass metabolism.
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Pharmacokinetic implicationsMetabolism
Clearance of (R)-fluoxetine is about four times greater than (S)-fluoxetine due to a higher rate of enzyme metabolism.
R-pantoprazole and R-Metoprolol are subjected to much higher EM/PM variability than their S-counterparts.
Chiral inversion:
Conversion of one enantiomer into its mirror image.
S-ibuprofen is the active form but significant R to S inversion takes place in the body. Therefore, ibuprofen in racemic form, exhibits 75% of the activity of the S-ibuprofen at the same dose level.
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Pharmacokinetic advantages of chirally pure drugs
Less complex pharmacokinetics
Reduced metabolic load over the enzymatic system
Less interaction potentiale.g. • (R)-fluoxetine inhibits CYP2D6, to a lesser extent than (S)-
fluoxetine. • Metabolism of R-pantoprazole is reported to be impaired to a
greater extent than S- pantoprazole in poor metabolizers.
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Pharmacodynamic implicationsEnantiomers bind to receptors stereoselectively
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Pharmacodynamic implications Contd..
The beneficial effects of a drug can reside in one enantiomer,
with its paired enantiomer having:
No activity
Some activity
Antagonist activity against the active enantiomer
Completely separate beneficial or adverse activity from
the active enantiomer.
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Pharmacodynamic implications Contd..
Examples: Only one isomer is active, the other is “inactive”
S-atenolol: beta blocking property resides in S-enantiomer.
Levocetirizine: R-enantiomer of cetirizine is active; the S-enantiomer being essentially inactive.
Levofloxacin: Activity resides in the S-enantiomerDexibuprofen, Dexketoprofen (Chiral inversion with
ibuprofen)
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Pharmacodynamic implications Contd..
Examples: One isomer is active, the other has “some activity”
R-ondansetron: More potent than the S- enantiomer.S-Pantoprazole: More potent than the R- enantiomer.Esomeprazole: More potent than the R- enantiomer;
increased bioavailability, less pharmacokinetic variability.
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Pharmacodynamic implications Contd..
Examples: Beneficial effects reside in one enantiomer, the other enantiomer having “antagonistic activity”
R-Salbutamol: Bronchodilator activity resides in (R)-salbutamol. (S)-salbutamol, indirectly antagonizes the benefits of (R)- salbutamol and may have proinflammatory effects.
R-Lipoic acid: R-lipoic acid is responsible for most of alpha-lipoic acid's beneficial effects. The S-form can oppose the action of the R-form.
Escitalopram
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Pharmacodynamic implications Contd..
Examples: Beneficial effects reside in one enantiomer, the other enantiomer having completely separate “beneficial activity”
Fluoxetine: Drug development of both enantiomers for different indications is underway (R-fluoxetine for depression and S-fluoxetine for migraine).
Propranolol: S-propranolol has beta blocking and membrane stabilizing property, R-propranolol has only membrane stabilizing property; the R-enantiomer may be useful in hyperthyroidism
Sibutramine: The R-sibutramine metabolite is under evaluation for the treatment of depression and the (S)-sibutramine metabolite for the treatment of erectile and ejaculatory dysfunction
Pharmacodynamic implications Contd..
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Pharmacodynamic implications Contd..
Examples: Beneficial effects reside in one enantiomer, the other enantiomer having “adverse activity”
S-Amlodipine: R-enantiomer thought to be responsible for pedal edema due to racemic amlodipine
(S)-Ketamine: post anaesthetic emergence reactions (hallucinations and agitation) predominantly associated with the R-enantiomer.
Levobupivacaine: Cardiotoxicity predominantly associated with the R-enantiomer.
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Examples: Beneficial effects reside in one enantiomer, the other enantiomer having “adverse activity”
S-Metoprolol: Beta-1 selectivity of S-metoprolol is similar to that of racemic metoprolol, while the R-enantiomer is almost non-selective and therefore may cause adverse effects related to beta-2 blockade
S-Oxybutynin: Equivalent antispasmodic activity with lower incidence of antimuscarinic side-effects than seen with RS-oxybutynin.
Pharmacodynamic implications Contd..
Toxicity • DOPA is a precursor of dopamine that is used
in the treatment of parkinson disease. Dopa when used under racemic form: d,l-dopa, but owing to grave toxicity (agranulocytosis) , therefore levorotatory form of L-dopa is used.
Advantages of chiral switch• Improved safety margin through increased receptor
selectivity and potency, and reduced adverse effects • Longer or shorter duration of action due to
pharmacokinetic considerations (e.g. half-life) resulting in a more appropriate dosing frequency
• Decreased inter-individual variability in response commonly due to polymorphic metabolism
• Decreased potential for drug-drug interactions.
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The guidelines strongly encourage the development of single isomers and discourage stereoisomeric (e.g., racemic) mixtures.
Approval could not be granted for a drug containing more than one isomer unless the pharmacokinetic and pharmacodynamic properties of each could be described and, more importantly, justified.
(Chirality 1992;338-40; http://www.fda.gov/cder/guidance/stereo.htm).
US - FDA’s Policy Statement
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US FDA’s Incentive To Promote Chirally Pure Drugs
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Strategies for development of chirally pure drugs
Chiral switch (CS)In a CS, one of the two enantiomers of an established racemate is developed as a new drug, with the expectation that the single-isomer form has advantages over the racemic parent in terms of efficacy and/or adverse effects.
Chiral metashift (CM)In a CM, a chiral metabolite of a drug is developed, in single-isomer form, as an agent with advantages over the parent. E.g. Zopiclone, Sibutramine
New single-isomer chemical entity(NSICE)Introduced as single enantiomers
Chiral Separation
Commercially available racemates
AmlodipineR-enantiomer S-enantiomer
Inactive as a Ca2+ channel blocker but may not be completely inert. Mainly responsible for blunting ofprecapillary postural vasoconstrictorreflex and for other local changes responsible for peripheral oedemadue to racemic amlodipine
Only vasoactive enantiomer of amlodipine longer plasma t1/2. Lesser intersubject variability in the clearance.Negligible incidence of peripheral oedema than the racemate
Resolution of edema due to Amlodipine after switching over to S-Amlodipine:
314
4
0
50
100
150
200
250
300
No.
of p
atie
nts
Before After S-amlodipineAdmn.
98.72 % reduction in peripheral oedema after switching over to S-Amlodipine
Overall incidence of edema with S-Amlodipine was 0.75 %( i.e. 14 out of 1859 patients)
JAMA-India 2003; 2(8): 87-92
Key points• S-Amlodipine in half dose is as effective as full dose
Amlodipine• Very less incidence of lower extremity edema as
compared to racemic amlodipine• Most of the patients who complained of edema with
racemic amlodipine were relieved of the ADR after switching over to S-Amlodipine
• Effective in ISH, elderly hypertensives, angina.
Atenolol
R-enantiomer S-enantiomer
Relatively stronger activity inblocking β -2 receptors than beta-1 receptors. Responsible for loss of cardioselectivity at higher doses of racemate
Predominantly responsible for cardiac beta blocking activity
Bupivacaine
R-enantiomer S-enantiomer
Cardiotoxic effects and toxic effects on the CNS
Less cardiotoxic effects and less toxic effects on the CNS in comparison withboth dextrobupivacaine andBupivacaine itself. Wide safety margin than the racemate
CetirizineR-enantiomer S-enantiomer
Smaller volume of distribution, small even than that of Cetirizine-confers improved safety because of low hemato-encephalic barrier passage and low cerebral receptor binding. Enhance peripheral receptor binding and improved overall selectivity specific to the H1 receptor than the racemate. Pharmacokinetic studies indicate improved safety profile
Inactive nature (larger-scale comparative studies are however, warranted to address the issue)
Ketamine
R-enantiomer S-enantiomer
Inhibits the elimination of S-Ketamine in the racemate
2-3 times more potent racemic ketamine. Eliminated more rapidly as a single enantiomer than as a component of the racemate. Incidence of psychotomimetic phenomena is negligibly less with S-ketamine in comparison to racemic ketamin
MetoprololR-enantiomer S-enantiomer
Relatively stronger activity inblocking β -2 receptor than β-1 receptors. Responsible for loss of cardioselectivity at higher doses of racemate. Clearance is slower than S-metoprolol in poor metabolizers, resulting in higher concentrations ofthe non-selective R enentiomer if a racemate is administered
Predominally responsible for cardiac β blocking activity. Ensures cardioselectivity even in poor metabolizers as concentrations of only the β-1 selective component would be increased. Avoids some harmful drug interactions with some drugs like cimetidine, ciprofloxacin and verapamil, which selectively increase the concentrations of nonselective R-metoprolol
Omeprazole
R-enantiomer S-enantiomer
Exhibits greater variability than S-isomer in poor versus extensive metabolizers of CYP2C19 substrates. More dependent on CYP2C19. This results in the less active R-enantiomer achieving higher concentrations in poor metabolizers, which may in the long term cause adverse effects like gastric carcinoids and enterochromaffin- like cell hyperplasia.
Could be metabolized by alternative pathways lie CYP3A4 andsulfotransferases. Clinical more effective than the racemate.
Ondansetron
R-enantiomer S-enantiomer
No QTc prolongation. Lesscardiotoxic than either S Ondansetron or racemic Ondansetron. More potent than the S-isomer.
Cause QTc prolongation
Salbutamol
R-enantiomer S-enantiomer
Bronchodilator activity Inactive as bronchodilator but not completely inert and can induce airwayhyper-reactivity, eventuallycontributing to increased morbidity andmortality in patients with asthma
Chirality! Today's and Tomorrows desirable way of treatment
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