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Lecture no 4


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Lecture no 4

  1. 1. Medicinal Chemistry Fourth Lecture
  2. 2. <ul><li>Physicochemical Properties of Drugs </li></ul>
  3. 3. Partition Coefficient of Drugs <ul><li>Partition Law: “ A given substance, at a given temperature, will partition itself between two immiscible solvents in a constant ratio of concentrations” </li></ul>
  4. 4. <ul><li>Consider 100 mg of a drug added to an immiscible mixture of a 50 mL organic solvent (e.g. octanol) and 50 mL of water in a separating funnel. </li></ul><ul><li>After the mixture was allowed to equilibrate, the mass of the drug in the organic phase was determined to be 66.7 mg. </li></ul><ul><li>The mass of the drug in the water phase will be </li></ul><ul><li>100-66.7=33.3 mg </li></ul><ul><li>Concentration of the drug in the organic phase will be </li></ul><ul><li>66.7/50 = 1.33 mg/mL </li></ul>
  5. 5. <ul><li>Concentration of the drug in the aqueous phase will be </li></ul><ul><li>33.3/50= 0.67 mg/mL </li></ul><ul><li>P = [Organic]/[Water]= 1.33/0.67= 2 </li></ul>
  6. 6. How Can the Partition Coefficient be Used? <ul><li>Prediction of: </li></ul><ul><li>Absorption </li></ul><ul><li>Distribution </li></ul><ul><li>Elimination </li></ul><ul><li>of the drug in the body. </li></ul><ul><li>Is the above given value of P pH dependent? </li></ul>
  7. 7. <ul><li>To ensure that the above equation applies in the case of: </li></ul><ul><li>Acidic substances (the pH of the measurement must be low) </li></ul><ul><li>Basic Substances (the pH of the measurement must be high) </li></ul><ul><li>Why ? </li></ul>
  8. 8. <ul><li>Alternatively (in the case of drug ionization): </li></ul><ul><li>The above expression is termed the “apparent partition coefficient (P app )” while the similar expression for the unionized drug is termed “the true partition coefficient”. </li></ul><ul><li>P app is dependent on the proportion of substance present in the solution which is pH dependent. </li></ul><ul><li>P app = P X f un ionized </li></ul><ul><li>f un ionized = 1, P app = P, the drug is unionized </li></ul>
  9. 9. <ul><li>Consider the following situation: </li></ul><ul><li>The previous drug is found to be 40 mg in the organic phase, while the remaining drug in the water phase is 66.7% ionized. </li></ul><ul><li>The mass of the drug in the water phase = 100-40 = 60 mg </li></ul><ul><li>The mass of the ionized drug in water = 60 X 0.67= 40 mg </li></ul><ul><li>The mass of the unionized drug in water = 60 X 0.33 = 20 mg </li></ul><ul><li>Concentration of the drug in the organic phase = 40/50= 0.8 mg/mL </li></ul>
  10. 10. <ul><li>Concentration of the unionized drug in water = 20/50 = 0.4 mg/mL </li></ul><ul><li>Concentration of the total drug in water = 60/50 = 1.2 mg/mL </li></ul><ul><li>The percentage of the drug extracted into the organic phase = (40 mg/100 mg) X 100 = 40 % </li></ul><ul><li>The partition coefficient of the unionized drug (the true P) is given by: </li></ul><ul><li>P = [drug] in organic phase/[unionized drug] in water </li></ul><ul><li>= 0.8/0.4 = 2 </li></ul>
  11. 11. <ul><li>P app = [drug] in organic phase/ total [drug] in water phase = 0.8/1.2 = 0.67 </li></ul><ul><li>P app can be checked: </li></ul><ul><li>P app = P X f unionized </li></ul><ul><li>0.67 = 2 X 0.33 </li></ul><ul><li>P values can vary from small fractions to several thousends therefore the log of P is usually used especially in QSARs </li></ul>
  12. 12. <ul><li>P represents a measure of the ease of movement of drugs through biological membranes. </li></ul><ul><li>The accuracy of the correlation depends on the system used as a model for the membrane. </li></ul><ul><li>n-octanol, chloroform, and olive oil are used to model the lipid component while water and buffered solutions are used for the aqueous medium. </li></ul><ul><li>n-octanol-water is the most commonly used model. </li></ul>
  13. 13. <ul><li>Matching the organic phase with the area of biological activity leads to a better correlation: </li></ul><ul><li>n-octanol gives the best consistency for the drugs that are absorbed in the GI tract </li></ul><ul><li>Less polar solvent like olive oil give more consistent correlation for drugs crossing the blood-barrier membrane. </li></ul>
  14. 14. <ul><li>SARs and QSARs </li></ul>
  15. 15. <ul><li>Compounds that are similar to pharmacologically active drugs are most likely to be active themselves. </li></ul><ul><li>These drugs may have: </li></ul><ul><li>1. Similar activity, different potency </li></ul><ul><li>2. Different activity </li></ul><ul><li>Structurally related activities are referred to as “ SARs” </li></ul><ul><li>These studies on the lead and its analogues may lead to the identification of the “pharmacophore” and the part of the structure that is related to the side effects. </li></ul><ul><li>This information can in turn be used to design drugs that are </li></ul>
  16. 16. <ul><li>More potent and which have fewer side effects. </li></ul><ul><li>SARs are usually carried out by making a small change to the lead and assessing the concomitant change in the biological activity. </li></ul><ul><li>These changes can be in: </li></ul><ul><li>The size and shape of the carbon skeleton </li></ul><ul><li>The nature and degree of substitution </li></ul><ul><li>The stereochemistry of the lead </li></ul>
  17. 18. <ul><li>The selection of the change depends on many consideration: </li></ul><ul><li>Activities of compound with similar structures </li></ul><ul><li>Biochemistry of the intended analogue. </li></ul>
  18. 19. Changing Size and Shape <ul><li>Can be done by: </li></ul><ul><li>Changing the number of methylene groups </li></ul><ul><li>Increasing or decreasing the degree of unsaturation </li></ul><ul><li>Introducing or removing a ring system </li></ul>
  19. 25. Introduction of New Substituents <ul><li>These substituents will either: </li></ul><ul><li>Replace an existing one </li></ul><ul><li>Occupy a previously unsubstituted position </li></ul><ul><li>A great deal of information has been collected over the years about the change of properties that will be caused by the introduction of new substituents. </li></ul><ul><li>This fact makes it possible to make some generalizations </li></ul><ul><li>Substituent choice will depend on the desired function </li></ul>
  20. 26. Incorporation of a group in an unsubstituted position <ul><li>Leads to change in the size and shape of the molecule </li></ul><ul><li>May Introduce a chiral center </li></ul><ul><li>May impose some conformation restrictions on some of the bonds of the analogue </li></ul><ul><li>May lead to: </li></ul><ul><li>increased rate of metabolism </li></ul><ul><li>Reduction in the rate of metabolism, or </li></ul><ul><li>Alternative route of metabolism </li></ul>
  21. 30. <ul><li>The End </li></ul>