301 Medicinal Chemistry of GORD/PU Flashcards
Drugs acting on GI system:
Antacids
Inhibitors of gastric acid secretion
Histamine (H2) receptor antagonists
Proton pump inhibitors
Anti-diarrhoeal drugs (loperamide)
Gastric acid secretion:
Parietal cell receptors
Mechanism
- Acetylcholine (M₃)
Histamine (H₂)
Gastrin (CCK₂) - Activation of these receptors stimulates the proton pump (H⁺/K⁺ ATPase).
This leads to H⁺ and Cl⁻ secretion into the stomach lumen → Formation of HCl (gastric acid).
Antacids MOA
Neutralisation of HCl in stomach
Reduced H+ conc.
Increases gastric pH
Antacid types
- Carbonates (CO3(2–)) [MgCO3 and CaCO3]
- CaCO3 + 2HCl → CaCl2 + CO2 + H2O - Hydrogencarbonates (HCO3−) [NaHCO3 and KHCO3]
- NaHCO3 + HCl → NaCl + CO2 + H2O - Hydroxides (OH) [Mg(OH)2 and Al(OH)3]
- Al(OH)3 + 3HCl → AlCl3 + 3H2O
Antacid adverse effects
Can cause constipation & diarrhoea
Excessive consumption can increase pH
Increased intake of metal ions (Ca2+, Na+, Al3+)
Discomfort due to CO2 production
Do not reduce acid secretion
Acid rebound (calcium carbonate)
Drug-drug interactions (DDIs)
Can affect absorption of other drugs
Increased GI pH alters:
- Degree of ionisation
- Integrity of enteric coatings
Complexes between drugs and metal ions
So avoid concomitant administration with enalapril, lansoprazole & hydroxychloroquine
Histamine and gastric secretion
Known to promote gastric secretion
- Basic centre (primary amine) so ionised to NH3+
- Imidazole ring
Acidic solutions and histamine
Primary amine is more basic as it has higher pKa
Histamine ionises 1 basic centre but in acid, both centres are ionised
H1 and H2 blockers
H1: antihistaminic or antiallergenic factors (ranitidine)
H2: GIT agonists
What do H1 antagonists need
Di-aryl
Flexible chain (can move like an axis)
Basic amino group
Diphenhydramine at physiological pH H1 and H2
H1 becomes positive charged
H2 does not hydrolyse NH
Development of cimetidine
First H2 receptor antagonist
Developed before molecular target was confirmed released in 1976
Became world’s biggest-selling prescription drug revolutionised ulcer treatment (bleeding)
Why was guanylhistamine formed from histamine?
A larger compound than histamine is needed to block the binding site which is the partial agonist (guanidine fragment which binds to histamine)
Not a pure antagonist because it is not available in physiological pH
Guanidine ionisation and being a partial agonist
Guanidine is easily ionised
Reacts with both regions (agonistic and antagonistic activity), making it partial
What are the 2 binding regions of H2 receptors responsible for? And guanine binding for both
1) responsible for agonistic activity, guanine reacts by binding hydrogen bonding
2) responsible for antagonistic activity, guanine reacts by ionic bonding
Why was SKF 91581 created after guanylhistamine from histamine?
Need to design compound which only reacts with antagonistic activity by hydrogen bonding (SKF91581) but had weak antagonist activity
When lengthening chain from guanylhistamine, it proved to have better antagonistic activity
Why was burimamide created from SKF 91581? (From guanylhistamine and histamine)
Lengthening chain made burimamide has 100x more potent properties than guanylhistamine
Adding methyl and sulphur to make metiamide makes is 10x more active
What is thiourea structure? And what does it cause?
H₂N−C−NH₂
But has thiourea which caused thrombocytopenia and kidney problems in patients even though it was more effective (toxic)
Why was thiourea replaced in SKF 91581 to burimamide?
Replace thiourea fragment with safer one (they reverted to guanidine analogue after metiamide (pKa of 12.5)), to avoid ionisation they need to raise pKa to 6.8
Why was CN added to cimetidine after the guanidine analogue?
CN group withdraws electrons and makes the centre more basic in cimetidine (Tagamet)
Why was guanidine so useful in cimetidine development?
Guanidine is basic so ionises easy (high pKa) but we need it to not ionise so easily in blood so make cimetidine
What modification to N⁰-Guanylhistamine gave partial agonistic activity?
Histamine modification
What was the main problem after achieving partial agonistic activity with N⁰-Guanylhistamine?
To completely remove agonist activity to get a pure antagonist
How is the agonistic effect achieved compared to the antagonistic effect in terms of bonding?
Agonistic effect is achieved through ionic interaction, while antagonistic effect is through hydrogen bonding
What change was tested in the structure for creating a pure antagonist?
Replacing the guanidine group with a neutral group that forms two hydrogen bonds
Which compound was created by replacing the ionizable guanidine moiety with thiourea?
SKF 91581
What modification in Burimamide led to enhanced activity?
Chain extension and addition of an N-methyl group
Why was Burimamide not suitable for clinical trials?
Its activity was too low for oral administration
Which derivative showed enhanced activity but caused side effects like kidney damage and granulocytopenia?
Metiamide
Why was thiourea proposed to be replaced in Metiamide?
Because thiourea is uncommon in human biochemistry and caused side effects
What analog was developed as an alternative to Metiamide’s thiourea?
Urea and guanidine analogues
Why did the guanidine analogue show less activity?
Due to its ionization in the physiological pH (pKa = 12.5)
Which analogue was developed to avoid the ionization issues with the guanidine group?
Cyanoguanidine analogue (Cimetidine)
How does the electronic withdrawing effect of CN group affect the guanidine group in Cimetidine?
It makes the guanidine group less basic and non-ionizable
What is the polarity and log P value of Cimetidine?
High polarity with log P = 0.4
What are the main structural properties of cimetidine that means it is ideal for ulcer treatment?
- Polar non-basic group required for H2 antagonism
- Cyano group is strong electron withdrawing making guanidino group effectively non-basic (non-ionisable)
- Fairly high polarity (log P = 0.4)
What does cimetidine inhibit? And what does this result in?
CYP-450 enzymes in liver
Enzymes involved in drug metabolism Inhibition of these by cimetidine may increase toxic side effects as increased blood levels of these drugs
Caution with cimetidine
When taken with diazepam, phenytoin, lidocaine, warfarin or theophylline
Why can cimetidine not be taken with warfarin?
Competitively inhibits in the blood, it gets taken up over warfarin and so warfarin is free in blood and incidence of bleeding increases
How did cimetidine become ranitidine? And why was this done?
Replaced imidazole ring with a furan ring bearing a nitrogen-containing substituent
Fewer DDIs, longer duration of action, 10x more active
Why does ranitidine need to be inspected after manufacturing?
Some compounds found NDMA (carcinogen) in 2019 so inspection to find NDMA form ((CH3)2NN=O) within it
What effect do famotidine and nizatidine show?
Have thiazole ring and H2 effect (antagonistic, polar non-basic centre and when hydrolysed becomes agonistic)
How does H2 antagonists act on proton pump?
Inhibit it, depletes gastric acid of protons and so decreases acidity (PPIs)
Proton pump inhibitors:
What stage are they part of?
What were they developed from?
- H+/K+ ATPase inhibitors, final stage of gastric acid release
- Failed anti-viral drug
Why did the failed antiviral become a PPI?
They had reduced acid secretion as a side effect in the antiviral
What is SOSA?
(selective optimisation of side activities) - compound which is originally designed for specific pharmacology but shows side activity for another pharmacology and focus on the side effect
Why was imidazole ring in CMN131 changed to a benzimidazole ring in H124/26?
Showed some activity but not a lot, then they changed to benzimidazole ring which had more active metabolite
Why was timoprazole changed to picoprazole?
Not strong enough so added substitutions to make stronger and not toxic (1st PPI tested in humans)
Inhibited iodine reuptake in thyroid gland which is side effect & so add more substitutions so more selective to PP
Picoprazole changed to omeprazole
More modification to increase basicity & activity then to omeprazole
Omeprazole structural features that make it a PPI
- Benzimidazole pKa = 8.7
- Pyridine pKa = 4.0
- Benzimidazole more basic so more likely iodised in physiological pH
- Greater proportion ionised in acidic conditions which is key to MOA
How is omeprazole activated?
Pyridinium sulphenamide structure reacts with cysteine in proton pump (SH on amino acids)
Bond is covalent (disulphide) on bottom structure so irreversible inhibition of the proton pump
What does the activated form of a Proton Pump Inhibitor (PPI) react with?
Accessible cysteine residues on the proton pump
Which cysteine residues are accessible on the proton pump?
Cys-813, Cys-892, Cys-821, and Cys-822
Which cysteine residues does Omeprazole react with?
Cys-813 and Cys-892
Which cysteine residues does Lansoprazole react with?
Cys-813, Cys-821, and Cys-892
Which cysteine residues does Pantoprazole react with?
Either Cys-813 or Cys-822
Which cysteine residue reacts with all PPIs?
Cys-813
Why are PPIs most active when parietal cells are secreting hydrochloric acid?
Because acid conditions are required to activate PPIs
Why are H₂ inhibitors contraindicated with PPIs?
PPIs are less active when parietal cells are in a resting state, and H₂ inhibitors reduce acid secretion, which would reduce PPI activity
How do PPIs achieve irreversible inhibition of the proton pump?
By forming a covalent disulfide bond with the proton pump
What determines the duration of PPI inhibition?
How quickly new proton pumps are generated by the cell
What is a prodrug?
Inactive drug needs an acidic medium to activate it into active form
Why is enteric coating needed on omeprazole?
Only need omeprazole in parietal cells to be activated by the acidic medium of parietal cell so need enteric coating to get it through the stomach acidic medium
Why can ranitidine (H2) and omeprazole (PPI) not be prescribed together?
Need acidic medium to activate PPI so giving H2 blocker will reduce acidic medium (reduce gastric secretions)
Omeprazole formulations
Enteric coated tablets & granules in capsules
Multi Unit Particulates Systems (MUPS) dispersible tablets
Dispersion in suitable vehicle (pH) (enteric coated granules)
What is the chiral centre of omeprazole?
S double bonded O
Why is S-omeprazole favoured over R-omeprazole?
S is less metabolised so less clearance, high bioavailability, less patient variability due to less metabolism
Nexium is S form on its own without the R form
Chiral switching
What is chiral switching?
Have two isomers but swap from one isomer to another in practice
What do all PPIs have?
Methylsulphinyl ‘linker’
Pyridine
Benzamidazole
What is H.Pylori treated with?
PPI and 2 antibiotics
Most common: omeprazole + clarithromycin + amoxicillin
Metronidazole replaces amoxicillin in penicillin allergic patients
What is revaprazan and how does it act on PP?
Potassium-competitive acid blocker (P-CAB) (antagonist)
Binds with high affinity to K+ site of H+, K+ ATPase, reversible antagonist
Competes with K+ into the parietal cell and so protons cannot leave the cell
Not approved in Europe or US
How do anti-motility drugs?
Increase motility of GIT
Opioid analgesic side effect is antimotility
Morphine analogues have same effect but no CNS activity, does not pass through BBB
Loperamides local effect on GIT without CNS side effects
- Tertiary amino group is basic (pKa = 8.6), approx. 90% ionised at physiological pH what limits BBB crossing
- Substrate for efflux protein P-glycoprotein (P-gp) what extensively prevents drug uptake into brain (becomes substrate for P-gp and takes drug back out of brain)
What does inhibition of P-gp allow?
Accumulation of loperamide in brain
Opioid CNS side effects (respiratory depression) so use of loperamide with P-gp inhibitors is contraindicated (Quinidine)
Why can loperamide and quinidine not be given together?
Will enter BBB and cause CNS effects
