Today & Tomorrow’s way of Treatment

What is Chirality ?
 An object is “chiral” if and only if it
is not super imposable on its
mirror image.
 Chirality changes the 3
dimensional interaction of similar
looking objects with its receptors
or immediate environment.
 Enantiomer:
– Single isomer not super-
imposable on its mirror image.
Molecules interact stereo specifically

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 Enantiomers Differ
• Only one isomer is active, the other is “inactive”:
• Levocetirizine (active),
• Levofloxacin (active)
• S-amlodipine (active CCB)

• One isomer is active, the other is more potent

• Esomeprazole (more potent)
• S-pantoprazole (more potent)

• Beneficial effects reside in one enantiomer, the other enantiomer having

antagonistic activity:
• Levo-salbutamol (bronchodilator without pro-inflammatory properties)

• Beneficial effects reside in one enantiomer, the other enantiomer having

completely separate beneficial activity:
• Dextropropoxyphene (analgesic); levopropoxyphene (anti-tussive)

• Beneficial effects reside in one enantiomer, the other enantiomer having

adverse activity:
• Esketamine (no hallucination/agitation),
• Levobupivacaine (no cardiotoxicity)
• S-metoprolol (beta-1 blocker); R-metoprolol (beta-2 blocker)

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“Too often, and even without it being noticed, data in
the scientific literature on mixture of stereoisomers,
racemates, are presented as if only one compound
were involved. The neglect of stereochemical aspects
of drug action …. degrades many pharmacokinetic
studies to expensive “highly sophisticated
pseudoscientific nonsense.”

50% impurity is not acceptable

“The development of “hybrid” drugs, presented as a

step forward in medicinal chemistry, tends to be step
backward in therapy.”
EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 1984, 26, 663-8
 US - FDA’s Policy Statement

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).
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 Chirally Pure CVS products
 Beta adrenergic Antagonists: S(-)Metoprolol, S(-)Atenolol

 Calcium Channel Antagonists: S(-)Amlodipine, Diltiazem

 Antiarrhythmic Drugs: Quinidine

 ACE Inhibitor: Captopril, Enalapril, Ramipril , Lisinopril,

Benazepril, Fosinopril , Perindopril

 Statins: Atorvastatin ,Simvastatin, Pravastatin, Lovastatin,

Rosuvastatin

 Anti-platelet: Clopidogrel

 Centrally acting antihypertensive: Methyldopa

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 Recent Chiral Switches
S-AMLODIPINE Anti-hypertensive
S-METOPROLOL Anti-hypertensive
S-PANTOPRAZOLE PPI
R-ONDANSETRON Anti-emetic
DEXRABEPRAZOLE PPI
ESZOPICLONE Non-barbiturate Hypnotic
DEXIBUPROFEN NSAID
DEXKETOPROFEN NSAID
R-SIBUTRAMINE Anti-obesity
S-ETODOLAC NSAID
ARMODAFINIL Narcolepsy 8
 Conclusions

 There is no place for racemates that cannot

justify the existence of the “isomeric ballast”

 50% impurity is not acceptable

 Chiral purification can help to improve the

pharmacokinetics and phramcodynamics of
racemates.