Rational drug design Flashcards
1
Q
What are PPIs (proton pump inhibitors) (4)
A
- An alternative approach to stop gastric acid secretion
- block the enzyme H+, K+ -ATPase, the proton pump
- Proton pumps exchanges potassium ions and hydrogen ions (protons)
- therefore inhibiting them decreases pH
2
Q
How was target identification achieved with PPIS (3)
A
- At the time, the proton pump was not known about
- Researchers just looked for compounds that block gastric acid secretion
- This is called phenotypic screening
3
Q
How was Hit-to-lead achieved for PPIs (3)
A
- A Hypothesis: it’s the thioamide that causes the liver toxicity
- To combat the toxicity other groups with sulfur in them was used
- After, make other heteroaromatic rings (aromatic rings with atoms other than carbon in them):
4
Q
How was lead optomisation achieved for PPIs (5)
A
- Studying the metabolism in dogs showed that S-oxidation was taking place (enzymes adding oxygen to the sulfur atom):
- This compound with the added heteroaromic ring is more active but blocks uptake of iodine in the thyroid
- Structure activity relationships showed that electron donating groups (alkyl or nitrogen or oxygen) made the compounds more active
- The metabolism of omeprazole (with enzyme-SH) is required for it to work – it is a pro-drug
- One enantiomer is more effective than the other
5
Q
H2 antagonists (histamine) target identification (7)
A
- Histamine is derived from the amino acid histidine.
- Histamine has 2 actions: gastric acid secretion & allergic hypersensitivity.
- Antihistamine stops allergic hypersensitivity but does not affect gastric acid secretion.
- H1 receptors cause allergic hypersensitivity reactions.
- H2 receptors cause gastric acid secretion.
- Nowadays there are 4 known types of histamine receptors.
- There was very little relevant information available to start the drug discovery process
6
Q
How was hit identification of H2 antagonists achieved
A
The “hit” in this case was histamine itself
7
Q
How histamine compounds were tested (3)
A
- Modern biochemical techniques not available
- The team developed an assay where histamine is perfused into the stomachs of anaesthetised rats then the pH of the GI tract above the stomach was measured
- This is very slow, few compounds can be tested, poorly reproducible and even in the 1970s and 80s would have involved a concerning number of animals
8
Q
How was hit-to-lead of H2 antagonists achieved (9)
A
- Simple changes suggest that it is possible to get selectivity for H2:
- 2-methylhistamine – stronger H1 response
- 4-methylhistamine – stronger H2 response
- Both are AGONISTS
- After 4 years of trying and more than 200 compounds, none showed enough selective H2 antagonism - chemistry
- A new more sensitive assay was developed and the compounds were retested - biology
- Many of the compounds were found to be agonists – Block histamine binding but cause an effect themselves (weaker than histamine usually)
- The compounds were too similar to histamine – basic side chains were the problem:
- Neutral compounds (thioamide) start to solve the problem: giving the compount weak antagonistic activity
9
Q
How was lead optimisation of H2 antagonists achieved (7)
A
- Neutral compounds (thioamide) start to solve the problem: giving the compount weak antagonistic activity
- Variations in the chain with the intention of making the imidazole (the ring) resemble histamine (more in Silverman and Holladay): adding Me to the thioamide making it thiourea and S in the middle of the carbon chain
- This compound was tested on patients, but some showed reduced white blood cell counts (granulocytopenia)
- A Hypothesis: the white blood cell effects are caused by the thiourea group:
- So, try bioisosteres!
- thiourea → N-cyanoguanidine, N-nitroguanidine
- Lipophilicity is important
10
Q
Cimetidine discovery (3)
A
- First marketed in the UK in 1976
- 12 years after beginning the search for H2 antagonists
- difference is N-cyanoguanidine at the end of the molecule
