GI Chemistry

Question 1

Inhibitors of gastric acid secretion

Answer 1

• H2 receptor antagonists

* Proton pump inhibitors

Question 2

List gastric Secretory Cells

Answer 2

• Mucous cells
• Parietal cells
• Enterochromaffin-like cells
• Chief cells
• Enteroendocrine cells

Question 3

Controlling acid secretion

Answer 3

Controlling the pH within the stomach is crucial when considering drug absorption and limiting damage to the organ. Acid is secreted by the parietal cells in response to a number of factors. It is worth noting here that pharmaceutical companies have taken on this task with different companies focusing on particular signalling mechanisms. The biochemistry of acid release is quite simple and follows a similar pattern to that observed for absorption and elimination in other cells within the GIT.

The proton pump pumps protons out of the parietal cell and potassium ions back in. This requires energy which is provided by hydrolysis of ATP to ADP, catalysed by ATPase; the proton pump is also often called H+/K+‐ATPase. Chloride ions depart through a separate ion channel and HCl is formed in the canaliculus. The K+ ions exit the parietal cell as counterions for the chloride ions and are then pumped back in, with a separate potassium ion channel being used for K+ ions leaving the cell.

Question 4

PPI - CMN131, H77/67, H124/26, Timoprazole, Picoprazole, H159/69, Omeprazole

Answer 4

CMN131 Originally developed as an antiviral drug
•Inhibits gastric acid secretion
•Liver toxicity due to the thioamide group

H77/67 Inhibits gastric acid secretion
•The pyridine ring and bridging CH2S moiety are important to activity

H124/26 Increase in activity due to the benzimidazole ring

Timoprazole formed by metabolism of H124/26
•Timoprazole is the active drug
•Pyridinylmethylsulfinyl benzimidazole structure
•Side effect ‐ inhibits iodine uptake by the thyroid gland

Picoprazole potent antisecretory properties over long periods of time
•No toxic side effects on the thyroid
•No other serious side effects

H159/69 substituents which increase the basicity of the pyridine ring are good for activity
•Promotes the mechanism of activation
•Methyl substituents at the meta position have an inductive effect
•Methoxy substituent ismore effective at para position than meta position
•Resonance effect increases electron density on the nitrogen
•H159/69 is potent but chemically too labile

• Substituents were varied to get the right balance of potency, chemical stability and synthetic accessibility
• Omeprazole was found to have the best balance

Question 5

Mucous cells secrete

Answer 5

• Mucous cells: release thick mucus to prevent auto digestion and bicarbonate

Question 6

What does acid catalyse

Answer 6

• Acid catalyses pepsinogen → pepsin

* [Pepsin] ↑ due to autocatalysis

Question 7

Parietal cells secrete

Answer 7

• Parietal cells: HCl and Intrinsic Factor

Question 8

Enterochromaffin-like cells secrete

Answer 8

• Enterochromaffin-like cells: histamine

Question 9

Chief cells secrete

Answer 9

• Chief cells: pepsinogen, gastric lipase

Question 10

Enteroendocrine cells secrete

Answer 10

• Enteroendocrine cells: gastrin from G cells, somatostatin from D cells

Question 11

Reagents used in synthesis of cimetidine

Answer 11

1) LiAlH4 or a) Na/NH3/t-Bu-OH b) MeOH/NH4Cl
2) HS/\/NH2.HCL , 48% aq, HBr reflux 18h
3) H3CS- SCH3-N-CN, EtOH, rt, 16h
4) CH3NH2, EtOH, rt, 2.5h