H2 and PPI med chem Flashcards
how does the parietal cell work normally
- stimulated by ACh (M3), gastrin (CCK2), histamine (H2)
- invagination
- Leads to release of protons via H+ K+ ATPase into canaliculus
- Combine with Cl- (also released from parietal cell via Cl ion channel) to form HCL
how do H2 antagonists work to reduce stomach acid
H2 antagonists stop the binding of histamine to H2 receptor on parietal cell
natural histamine structure
imidazole ring - exists as 2 tautomers
aliphatic amine - charged at physiological pH
H1 agonist SAR
ring separated from positively charged N by 2C spacer
variation possible in aromatic ring
H2 agonist SAR
ring separated from positively charged N by 2C spacer
heteroaromatic ring must retain amidine group
H2 antagonist SAR
- Ketoaminal group is optimal for binding
- Sulphur group in chain increases activity
- More hydrophobic ring reduces activity
- Ring does not have to be imidazole!
- Substitution pattern matters but groups can be changed
effect of cimetidine on CYP450
inhibitor!
proton pump MOA
Forms disulphide bond with one or more of three cysteine residues on proton pump- irreversible!
why can proton pump inhibitors be taken orally
not charged and lipophilic
how are proton pump inhibitors activated
- PPI protonates benzimidazole ring
- Intramolecular reaction - 5 membered ring forms
- Benzimidazole ring reformed - formation of sulphonic acid derivative
- 2nd intramolecular reaction forms cationic pyrimidine
Disulphide bond formed from thiol of proton pump - inhibited enzyme
omeorazole SAR
- Substituents increasing basicity of pyridine ring = good
- Methyl at meta are inductive
- Methoxy are more effective at para then meta
- Sulfoxide and pyridine N essential for activation
- Ome in benzimidazole ring gives best balance of stability and potency
- benzimidazole ring
