Andy Watts - Basic principles of drug design 2 - Cimetidine

Question 1

List 3 properties of druggable targets

Answer 1

1) Usually a protein
2) Leads to biological response
3) Does not cause toxicity

Question 2

What is a drug molecule?

Answer 2

• Possesses one or more func groups positioned in three dimensional space
• On structural framework that holds func group in defined position
• Enables molecule to bind specifically to targeted biological macromolecule (receptor)

Question 3

Talk through the first part of discovering H2 receptor antagonists…

Answer 3

• Knew that the thought, smell or taste of food causes gastric acid secretion and pepsin release
• Prior to and during meals acid released and pH can of stomach can fall to 1-2
• ACh (secretagogue) activates cholinergic receptors of parietal cells leading to release of gastric acid into stomach
• Hormone histamine (secretagogue) stims release gastric acid by specific receptor interaction
• THE RECEPTOR WAS NOT KNOWN

Question 4

Talk through the second part of discovering H2 receptor antagonists…

Answer 4

• Identified Histamine receptor
• Wanted to identify specific antagonist of histamine receptor to suppress gastric acid rel by histamine
• Hypothesis = 2 diff receptors H1 (antihistamines) and H2 (involved in gastric acid secretion)
• Lead compound used = HISTAMINE

Question 5

What is the structure of Histamine?

Answer 5

• Imidazole ring = scaffold

- Amino group = functional group

Question 6

What technique was used to discover Cimetidine?

Answer 6

Rational Drug Design

- Before molecular modelling, protein crystallography and genetic engineering

Question 7

Talk through the third part of discovering H2 receptor antagonists…

Answer 7

• 4-methylhistamine found to be a highly selective agonist, stimulating gastric acid release
• Had weak other actions of histamine
• Supported hypothesis that there is a second receptor- H2
• 2 conformations but other disfavoured due to steric hinderance from CH3 group (conformational blocker)
  (amino group and chain outwards not pointing up)
• This selectivity suggests that histamine must adopt two diff conformations for H1 and H2 receptor

Question 8

Talk through the fourth part of discovering H2 receptor antagonists…

Answer 8

• N alpha-guanylhistamine found to be a weak antagonist of gastric acid release (also partial agonist)
• Prevent histamine binding
• H2 receptor model developed based on antagonist and agonist binding regions
• Made other derivatives of guanyl groups to see which properties important for binding
• Saw needed imidazole ring and guanidine group needed for antagonist properties

Question 9

Talk through the fifth part of discovering H2 receptor antagonists…

Answer 9

• Burinamide was discovered
• Moderate antagonist with NO AGONIST ACTIVITY
• Functional group binds in antagonist site - proves H2 receptor exists
• Too weakly active for oral admin
• Structure? - imidazole with 4 carbons NH, C, double bond S and NHMe

Question 10

Talk through the 6th part of discovering H2 receptor antagonists (optimisation)

Answer 10

• Burinamide was found to be too basic (ionised at phys pH whereas histamine is unionised)
• Thiaburinamide synthesised and displayed enhanced antagonistic activity
• S group is EWG so made imidazole less basic reducing pKa

Question 11

Talk through the 7th part of discovering H2 receptor antagonists…

Answer 11

• Imidazole ring found in two tautomeric forms so if one form favoured for activity then modify struc to favour that form
• N tao - H is favoured tautomer in histamine (more basic)
• Augment the structure by placing EDG at position 4 of imidazole ring
• This makes it more basic though
• Despite the fact that it’s pKa is higher than desired, it is protonated in the correct position so activity is higher
• This is METIAMIDE
• More active than burinamide but unacceptable side effects - kidney damage

Question 12

Talk through the 8th part of discovering H2 receptor antagonists…

Answer 12

• Metiamide toxic to kidneys
• Thiourea group not especially common in human biochem
• Could be reason for toxicity - toxicophore
• Also excessive conformational isomerism around thiourea group so more motivation to replace it (only 1/4 binds and is active)
• Ideal functional group to replace would be guanidine as favourable toxicity BUT
• Already tried guanidine and weakly active as high basicity
• Appending cyano or nitro group to guanidine attenuates basicity!
• Cyano group is EWG so reduces basicity - better abs

MAKES CIMETIDINE!

• Strong selective H2 antagonist
• Inhibits gastric acid release
• No serious side effects

Question 13

How does Cimetidine undergo metabolism?

Answer 13

• Oxidation of sulphur (S=O)
• Hydroxylation of CH3 group (-OH)
• Both metabolites are more hydrophilic than parent
• More soluble for excretion

Question 14

How does Ranitidine differ from Cimetidine?

Answer 14

• Ten times more active
• Fewer side effects
• Lasts longer
• Cyanoguanidine replaced by CHNO2
• Furan ring with NMe2 replaces imidazole
• N takes place in binding that the imidazole does

Question 15

What now supersedes the use of H2 antagonists?

Answer 15

• Proton pump inhibitors

Question 16

How do PPIs work?

Answer 16

• Protons needed for HCl production in parietal cells come from water and CO2 catalysed by carbonic anhydrase
• Protons produced exported from cell using enzyme complex called proton pump
• Inhibit this and less H+ for production of HCl

Question 17

Why are PPIs preferred over H2 antagonists?

Answer 17

• Act at the end of a pathway
• Operates in final stage of HCl release
• Fewer side effects
• Better target than H2 receptor as Histamine just one of several secretagogues