Transcript Chirality - Today & Tomorrow's way of Treatment

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 superimposable 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
S-METOPROLOL
S-PANTOPRAZOLE
R-ONDANSETRON
DEXRABEPRAZOLE
ESZOPICLONE
DEXIBUPROFEN
DEXKETOPROFEN
R-SIBUTRAMINE
S-ETODOLAC
ARMODAFINIL
Anti-hypertensive
Anti-hypertensive
PPI
Anti-emetic
PPI
Non-barbiturate Hypnotic
NSAID
NSAID
Anti-obesity
NSAID
Narcolepsy
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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.
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