1. Chap 6. pKa 2013. 10. 11 Lee, Sang-Hwi

2. Overview  Medicinal chemists can modify the acidic or basic substructures on the scaffold in order to obtain the desired pKa, which affects solubility and permeability.

3. 6.1 pKa Fundamentals As pH (↓) : neutral acid molecules [HA] (↑) anionic acid molecules [A−] (↓) in solution. Acids with a lower pKa are stronger (greater tendency to form A−). 1) Acids 2) Bases As pH (↓) : neutral base molecules [B] (↓) cationic base molecules [HB+](↑) in solution. Bases with lower pKa are weaker (lower tendency to form HB+). HA = H + + A - Ka = [H + ][A - ]/[HA] pKa = -log Ka pKa = -log([H + ][A - ]/[HA]) HB + = H + + B Ka = [H + ][B]/[HB + ] pKa = -log Ka pKa = -log([H + ][B]/[HB + ]) Ka : acid dissociation constant acid ionization constant

4. The Henderson-Hasselbach equation

5. 6.2 pKa Effects Ex) Acidic compound (pKa 5) : pH (↑)  Permeability(↓), Solubility (↑) (↓) (↑)

6. 6.3 pKa Value

7. 6.3 pKa Case Studies

10. Basic drugs tend to penetrate the blood–brain barrier(BBB) more effectively than acids do.

11. Effect of pKa in water solubility of bile acids pKa(↓), acidity(↑)  Solubility (↑) Basicity (↑)  Solubility (↑)

12. Permeability (PAMPA assay) PAMPA : parallel artificial membrane permeability assay

13. 6.4 Structure Modification Strategies for pKa EDG and EWG can be added or removed to add electron density at the acid or base, depending on the desired effect. For example, 1)The strength of an acid  halogen(s) or EWG  increase  aliphatic groups  little effect.  Removing EWG  decrease 2) The strength of a base aromatic group (e.g., aniline).  decreased (The lone pair is delocalized into the aromatic ring.) aliphatic groups  slightly decreased The basicity of an aniline can be increased with attachment of a methoxy group, which donates electrons, or it can be decreased with the attachment of a nitro group, which withdraws electrons. It is important to remember that structural modifications that increase solubility will also decrease permeability.

14. Problems