1. Today & Tomorrow’s way of Treatment

2.  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. What is Chirality ?

3. 3 Molecules interact stereo specifically

4. 4 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)

5. “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.” “The development of “hybrid” drugs, presented as a step forward in medicinal chemistry, tends to be step backward in therapy.” 50% impurity is not acceptable EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 1984, 26, 663-8

6. 6 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

7. 7 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

8. 8 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

9. 9 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.