8. Medicinal Chemistry of Proton Pump Inhibitors & H2 Antagonists Flashcards
Gastric acid release
- HCl is a key component of gastric juice
- Secreted from parietal (or oxyntic) cells
- Stomach also secretes a layer of mucus to protect itself from acid
- Bicarbonate ions are released & trapped in the mucus
+ This leads to a pH gradient within the mucus layer
+ Help maintain intracellular pH in parietal cells
Acid generation
- H+ is generated through action of carbonic anhydrase (CA)
- CA catalyses the formation of carbonic acid from H2O & CO2
- Carbonic acid then dissociates into proton (H+) & hydrogen carbonate (HCO3-)
- HCO3- is exchanged for chloride ions (Cl-)
Acid release
H+ generated by carbonic anhydrase must be shuttled out of the parietal cell
- Proton pump on canalicular membrane pumps H+ out of cell & K+ into cell
+ Requires energy (ATP)
+ K+ pumped back in (moves in cycle)
- Cl- & K+ (as counter ion) flow out their ion channel
- Cl- & H+ generate HCl
Receptor control (3)
Parietal cells have 3 different receptors which control acid secretion
- Muscarinic type receptor – acetylcholine agonist
- Released by autonomic nervous system in response to the sight, smell or though of food - CCK2 receptors – gastrin agonist (peptide hormone)
- Released when food is present in the stomach - H2 receptor – histamine agonist
- Targeted by H2 antagonists
Peptic ulcers - overview
Erosion of the mucous membrane in the stomach
- Pain caused by irritation of the exposed surface by stomach acid
- If left untreated, could result in severe bleeding or even death
Causes are H. pylori or the use of NSAIDs
- COX-1 enzyme synthesised prostaglandins that inhibit acid secretion & protect stomach mucosa
+ Inhibition of COX-1 by aspirin causes increased gastric acid release & further aggravation of ulcer
PUD Treatments
Conventional treatment in early 1960s was neutralisation of gastric acid with antacids
- Large doses required -> unpleasant side effects
- Short duration of action & rigid diet requirements
H2 antagonists developed in the 1960s to reduce gastric acid secretion
PPIs introduced in the 1980s
- More effective than H2 antagonists
- Used alone for treatment of ulcers caused by NSAIDs
- Used in combination with antibiotics for ulcers where H. pylori infection is causative
H2 Antagonists
- Known from experimental data that histamine stimulated release of gastric acid
- Antihistamine should then in theory decrease/block gastric acid release
+ BUT conventional antihistamines at the time (1960s) had no effect - Proposed & later validated that there was more than one type of histamine receptor – H1 & H2 (histamine endogenous ligand at both)
+ Antihistamines that were available in 60’s (aimed at treating allergic reactions/irritations) were selective for H1 receptors
+ Gastric acid secretion is modulated by H2 receptors - Hundreds of compounds were prepared in the search for an H2 antagonist
Histamine agonist interactions
- Histamine side chain is charged at physiological pH
- Histamine binds to H2-receptor using ionic & H-bonding interactions
+ Charged amine with ≥ 1 proton required
+ Flexible chain required
+ Heterocycle with N-atom ortho to side chain required
Antagonist development (cimetidine)
How to transform an agonist to an antagonist?
- Probe for an additional binding site that prevents receptor activation (e.g. via conformational change)
Removing agonist activity?
- Extend flexible side chain
Cimetidine developed as H2 antagonist without side effects
- Methyl group: Small EWG -> promotes protonation of neighbouring N atom by induction
- Sulphur atom: Electronegative so act as EWG to lower pKa of imidazole -> uncharged imidazole
- Extended side chain: Allow guanidine group to reach antagonist binding site
- Cyano-guanidine group: String EWG so reduces basicity of N atom to promote H-bonding with antagonist region
Proton pump inhibitors (PPIs)
- All PPIs have a pyridyl methyl sulfinyl benzimidazole
- PPIs act as prodrugs that are activated at their site of biological target
E.g. [Pantoprazole], omeprazole, esomeprazole, [rabeprazole], lansomeprazole, dexlansoprazole, [ilaprazole]
Mechanism of action - prodrug activation (PPIs)
- PPIs are prodrugs & free bases (lipophilic) at blood pH (7.4)
- Become ionised in highly acidic environments e.g. canaliculi of parietal cells
- Ionised form cannot cross back into cell -> 1000-fold accumulation in canaliculi
- Ionisation triggers rearrangement -> active form
- Active form of PPI reacts with cysteine on proton pump
+ Irreversible activation of proton pump
Tolerance
PPIs have very few side effects because of their MoA:
- Target H+/K+ ATPase only present on parietal cells
- Canaliculi are the only area in the body with pH 1 – 2
- Drug accumulates at target site due to ionisation
- Ionisation only occurs when cells are actively secreting HCl
- Drug is rapidly activated close to target
- Reacts rapidly with the target
- Drug is inactive at physiological pH (7.4)
Formulations of PPIs
- Most PPIs are administered orally
- Use of enteric coating to prevent activation in acidic contents of stomach
+ Coating stable to gastric acid
+ At higher pH (~7-8) they break down & release the drug
+ Released in intestine where it is absorbed by blood supply and carried to parietal cells
Discovery & development of PPIs (Refer to lecture notes)
- Initially designed as an antiviral drug in 1970s
+ Found to inhibit acid secretion
+ BUT also exhibited toxicity to liver - Thioamide group causes side effect
+ Analogues were made to mask this group - Thioamide was masked as a cyclic thiourea
- Addition of a fused benzene ring improved activity (i.e. from an imidazole to a benzimidazole)
- Metabolism studies revealed that a sulfoxide metabolite was more active
- BUT toxicological studies in preclinical trials of the sulfoxide (timoprazole) revealed inhibition of iodine uptake by thyroid gland
- Analogue development showed that by placing substituents on the aromatic rings, antisecretory properties were retained
+ BUT iodine uptake was no longer inhibited - para-Alkoxy substituents on the pyridine ring were found to increase activity
+ H159/69 was extremely potent, but also too chemically labile - Substituents on aromatic rings varied to balance potency vs stability
- Omeprazole was launched in 1988
- Blockbuster – world’s biggest-selling drug in 2000
+ > 8.5 billion NZD in sales worldwide
Structure-Activity Relationships – Pyridyl substituents (refer to lecture notes)
All clinically approved PPIs have methyl groups & para-alkoxy group on pyridine ring
- Methyl EDGs increases the basicity of the N atom by resonance
- para-alkoxy group increases the basicity of the N atom by resonance
N of pyridine ring acts as a nucleophile during activation
- Increased nucleophilicity -> increased activity
para-alkoxy group increases the basicity of the N atom by resonance
- N of pyridine acts as nucleophile during activation
- Increased nucleophilicity -> increased activity
ortho-alkoxy group would be too bulky -> hinder mechanism
meta-alkoxy group would not put negative charge on N
