Chiral drugs

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  • 1. CHIRAL pharmacology By :- Swati datta Pharmacology (M.Pharm,Ist year)
  • 2. RECOGNITION OF CHIRALITY  Chirality is the fundamental property of 3 –dimensional object.  Chiral chemistry was identified by Lowis pasteur when in1948,for the first time seperated the 2- isomers of sodium potassium tartarate. • He found that the two isomers were identical in physiochemical properties but different in their ability to rotate plane polarized light.
  • 3. WHY STUDYING STERIO CHEMICAL FEATURES IS IMPORTANT  Biological Activity may reside in only one of the stereoisomer.  Stereoisomer's may show essentially similar qualitative And quantitative activity.  Isomer may exhibit similar qualitatively but different quantitatively activities.  Isomer may show distinct pharmacological activity.
  • 4. CHIRALITY • Property of a compound whose molecules are not super imposable on their mirror images. • Chirality = Handedness. • Necessary condition for existence of enantiomers.
  • 5. • Same molecular formula, same functional groups. • Differ in the way atoms are oriented in 3 dimensions. STEREOISOMERS ASYMMETRIC CARBON ATOM • Carbon atom to which 4 different atoms or groups are attached. Cl F Br H
  • 6. The Two Types of Stereoisomers  Geometric isomers  Optical isomers
  • 7. Geometric Isomers Cis (on the same side) Trans (across/opposite sides)  Cis-2-butene  Molecular Formula- C4H8  Structural Formula- CH3CHCHCH3  Trans-2-butene  Molecular Formula- C4H8  Structural Formula- CH3CHCHCH3
  • 8. Geometric Isomers and Drugs  Because geometric isomers have different chemical and physical properties, they act differently as drugs in our bodies as well. Example : •cis-platin used for chemotherapy - it can enter cancer cells and interact with DNA •Trans- platin - not active
  • 9. Optical Isomers Optical isomers  have a chiral center  non-super imposable mirror images
  • 10. Optical Isomers Terminology Chiral: if a molecule is chiral ( or displays chirality) this means the molecule has two optical isomers Chiral centre: the central carbon in an optical isomer with four bonds each attached to a different group. Enantiomer: another name for a molecule that is found in optical isomers. For example, ibuprofen has a two enantiomers, a left rotating enantiomer and a right rotating enantiomer. Racemic mixture: A mixture of 50% left rotating and 50% right rotating optical isomers
  • 11. ENANTIOMERS • Stereoisomers that are mirror images of each other. • Molecule and mirror image cannot be superimposed into each other even after twisting and turning them. • Identical physical and chemical properties • Dextrorotatory ("+" / “d” form) - clockwise direction. • Levorotatory ("-“ / “l” form) - anti-clockwise direction.
  • 12. DIASTEREOMERS • Stereoisomers that are not mirror images of each other. • Similar chemical properties but different physical properties. • Is an equimolar solution of the two enantiomers. • Shows no optical rotation. RACEMATE
  • 13. R/S SYSTEM a = 1; b = 2 ; c = 3 ; d = 4 • Priority of an atom is determined by its atomic number • Order of substituents going from highest to lowest priority. • Clockwise – R (rectus). • Anticlockwise – S (sinister). • Unless established experimentally no idea whether (+) or (-) rotation is associated with R or S configuration.
  • 14. Arthur r. Cushny & “ChirAl” Pharmacology 1866 - 1926 • (-)-Hyoscyamine almost exactly twice as active as atropine [( )- hysocyamine] (1904). • (-)-Adrenaline twice the potency of ( )-adrenaline as a vasoconstrictor (1908). (-)-enantiomer 12-15 fold more potent than (+)-adrenaline on sympathetic vessels (1909). • Biological Relations of Optically Isomeric Substances (1926).
  • 15. Cushny & “ChirAl” phArmACology  Believed that the “receptor” was chiral and combined with the enantiomers of the drug to produce diastereoisomeric drug – receptor complexes.  “---- difference in action lies not in the facility with which the chemical combination is formed, but in the physical characteristics of the resultant compound” (Cushny, 1926).
  • 16. STEREOPHARMACOLOGY • Affinity of a drug for a specific receptor and its intrinsic activity are related to its chemical structure. • Drug – receptor interactions are stereo selective. • Minor changes in drug molecule structure. • Major changes in pharmacological properties.
  • 17. Why do we care about this subtle form of stereoisomerism?  Biomolecules (sugars, amino acids, DNA, proteins, steroids) are chiral – Proteins are built from L-amino acids, which implies that enzymes – the catalysts of nature - are chiral – Also, receptors (drug, taste, biopharmaceuticals, agrochemicals) are chiral and the natural ligand to a receptor is often only one specific enantiomer – This is why mirror image molecules can have radically different activities (effectivity, toxicity, taste) in the body.
  • 18. Right-handed and left-handed molecules interact with living systems in very different ways and results for example in: olfactory sensors are chiral (R) CH3 O H (S) CH3 HH2C CH3 CH2 H3C O Mirror plane (R) Spearmint oil (S) caraway oil − Different smell
  • 20. Biological Discrimination
  • 21.  1987 • 57% marketed drugs were chiral. • 2% single enantiomers.  2006 • 80% drugs approved by the FDA were chiral. • 75% single enantiomers. CURRENT STATUS OF CHIRAL DRUGS
  • 22. − In 2000, 40% of drugs on sale in the US were single enantiomer-based. − In 2004, about 80% of drugs entering market are single enantiomer variants − FDA now requires information about the structure and activity of each isomer present in a racemic mixture of a new medication.
  • 23. What sparked the change???? • 1987 – change in FDA regulations. • Inclusion of information on the enantiomer composition of chiral compounds in new-drug applications.
  • 24. THALIDOMIDE • One asymmetric carbon atom, exists as 2 enantiomers • S-Enantiomer → sedative • R-Enantiomer Teratogen Phocomelia S thalidomide R thalidomide teratogen
  • 25. CHIRAL INVERSION • Unique metabolic pathway. • Enzymatic or non-enzymatic. • Involves unidirectional conversion of one enantiomeric form to another. R → S
  • 26. CHIRAL SWITCH • Development of a single enantiomer from a previously marketed racemate. • Resulted in a number of agents being re-marketed as chiral drugs. • Same or similar therapeutic indications. • Novel indications for old compounds.
  • 27. β2 ADreNErgic recePTOR AGONIST  Salbutamol • Salbutamol →Mixture of (R)-salbutamol and (S)-salbutamol • Levosalbutamol is the (R)-enantiomer → active bronchodilator. Racemic and (S)-Salbutamol • Induce airway hyper responsiveness. • Increase sensitivity to allergen challenge. • Inhalation of levosalbutamol→ greater bronchodilatation than the equivalent dose of the racemate. R SR S
  • 28. CALCIUM CHANNEL BLOCKER  Verapamil • (S)-verapamil : vasodilating , cardiac antidepressant properties. • (R)-verapamil : a vasodilating drug. • Verapamil blocks the P170 glycoprotein. • Interaction is non stereoselective. • Partially reverse multiple drug resistance of cancer cells. • R-verapamil might be expected to be more beneficial.
  • 29. S-AMLODIPINE • S-Amlodipine → active calcium channel blocker. • R-Amlodipine → inactive as calcium channel blocker. • Mainly responsible for peripheral edema. • Treatment of hypertension. • S-Amlodipine is effective at half the dose of racemate. • Incidence of peripheral oedema is negligible.
  • 30. • Treatment of normotensive angina patients. • S-Amlodipine is effective at half the dose of racemate. Cont..
  • 31. LOCAL ANAESTHETIC Levobupivacaine • Cardiotoxicity of the drug : R-enantiomer. • Levobupivacaine - „S‟ enantiomer of Bupivacaine. • Moderately more potent. • Significantly reduced negative inotropic effect . Levobupivacaine is less cardiotoxic.
  • 32. SELECTIVE SEROTONIN REUPTAKE INHIBITOR Escitalopram • S-enantiomer of Citalopram. • Doses that show improvement in depressed patients. 10 mg / day – „S‟ enantiomer 40 mg / day – racemate • Other advantages of Escitalopram. • Faster onset of action. • Reduction in side effects. • Improved tolerability profile. S R
  • 33. ANORECTIC AGENT  Sibutramine • Activity of racemic sibutramine – active metabolites. • R-sibutramine metabolite are More potent in the inhibition of monoamine uptake. Greater anorexic potency. Under evaluation for treatment of depression. Single enantiomer of metabolite - treatment of both obesity & depression.
  • 34. NON-STEROIDAL ANTI-INFLAMMATORY DRUG  Dexibuprofen • Inhibition of cyclooxygenase activity – „S’ enantiomer. • 60% of R enantiomer undergoes chiral inversion to the active S-enantiomer. • chiral Dexibuprofen (1200 mg daily) was better than racemate (2400 mg daily). • Highly effective NSAID. • Low adverse effect profile . **
  • 35. ADVANTAGES OF CHIRAL DRUGS • Chiral drug is a single agent instead of a mixture of two distinct drugs. • Simplifies the interpretation of the Basic Pharmacology. • Greater selectivity for their biological targets improved therapeutic indices and reduced adverse effects. • Longer or shorter duration of action - more appropriate dosing frequency. • Decreased inter individual variability.
  • 36. SOME DRUGS ARE BETTER AS RACEMATES  BLOCKERS • blockers currently used contain at least one chiral center. • Most are marketed as racemates. -
  • 37.  Labetalol • Two chiral centres ; four stereoisomeric forms. • R, R-isomer : b -blocking property • S, R-isomer : a -blocking property • Remaining isomers : inactive • Dilevalol ( R,R-isomer ) – elevated liver function tests. • Chiral dilevalol was withdrawn.