Chiral drugs

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

http://en.wikipedia.org/wiki/Threose

http://en.wikipedia.org/wiki/Erythrose

http://en.wikipedia.org/wiki/File:DThreose_Fischer.svg

http://en.wikipedia.org/wiki/File:DErythrose_Fischer.svg

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.

http://www.physics.upenn.edu/~kamien/chiralweb/kelvin.html



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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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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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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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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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


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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.


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


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


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


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


No QTc prolongation. Lesscardiotoxic than either S Ondansetron or racemic Ondansetron. More potent than the S-isomer.

Cause QTc prolongation

Salbutamol


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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Health & Medicine

Chiral drugs