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General principles of structure activity relationship (sar)
- 1. General principles ofStructure- Activity Relationship (SAR)
- 2. Contents …. • Introduction •History • Need of SAR • The size and shape of the carbon skeleton • The stereochemistry of the lead • The nature and degree of substitution • Summary
- 3. SAR • Chemical /3D structure of a molecule and its biological activity. • Affinity and intrinsic activity - chemical structure Minor modifications in the drug molecule Major changes in its pharmacological properties
- 4.
- 5. History • Brown andFraser in 1869 • Compounds containing tertiary amine groups Muscle relaxants (quaternary ammonium compound)
- 6. NEED OF SARSTUDY • A study of the structure–activity relationship is mainly done by lead molecule. • It is used to determine pharmacophore, unwanted side effects • To develop a new drug that has increased activity
- 7. NEED OF SARSTUDY • To determine some different activity from an existing drug • To fewer unwanted side effects • To know the changes in pharmacological properties by performing minor changes in the drug molecule
- 8. These changes maybe conveniently classified as changing • The size and shape of the carbon skeleton • The stereochemistry of the lead • The nature and degree of substitution
- 9. 1. Changing sizeand shape • No of methylene groups in chains and rings • Increasing or decreasing the degree of unsaturation • Introducing or removing a ring system
- 10. Examples of thevariation of response curves with increasing numbers of inserted methylene group 4-alkyl substituted resorcinols
- 11. Number of methylenegroups….. Changing the No of CH2 Change in activity
- 12. The degree ofunsaturation Prednisone ↑double bond - ↑ rigidity
- 13. Addition of ring…. ROLIPRAM 3,4dimethoxy phenyl butyrolactam (Antidepressant)
- 14.
- 15.
- 16. 2. The stereochemistryof the lead • Enantiomers – Isomers whose three dimensional arrangement of atoms results in non-superimposable mirror images
- 17. The stereochemistry ofthe lead • These compounds have identical physical chemical properties • Rotate plane polarized light to opposite directions • significant differences – Absorption (specially active transport) Serum protein binding and metabolism Different side effect or toxicity
- 18. Variations in thebiological activities of stereoisomers 1. Activity + potency = equal • R and S isomer of chloroquine
- 19. Cont…… 2. Activity ofdifferent type S –Ketamine – anesthetic R –Ketamine –little anesthetic action +antipsychotic
- 20. Cont……. 3. No activity S-alpha methyl dopa is antihypertensive R-isomer inactive
- 21. Cont……. 4. Active butdifferent side effects S – isomer of thalidomide –sedative + teratogenic
- 22. 3. Introduction ofnew substituents
- 23.
- 24. 1. Loss ofactivity
- 25. 2. Less sideeffects
- 26. 3.Enhancement of activitydepending on position clonidine .01mg/kg 3 mg/kg
- 27. The introduction ofa group by replacing an existing group • concept of isosteres - Isosteres are atoms, molecules, or ions of similar size containing the same number of atoms and valence electrons. - similar pharmacokinetic and pharmacodynamic properties
- 28. Examples of drugsdiscovered by isosteric replacement
- 29.
Editor's Notes
- #4 based on altered affinity for one or more receptors
- #7 suboptimal structure that requires modification to fit better to the target. .A pharmacophore is an abstract description of molecular features which are necessary for molecular recognition of a ligand by a biological macromolecule
- #11 4-alkyl substituted resorcinols
- #13 Introduction of double bond increases the rigidity of a structure….