PPIs

• To develop drugs we need to understand the relationship between what?

  Structure and activity (biological effects)
• what is the best way to understand toxicity with drugs in humans?

  to test its toxicity in animals and other human toxicity models to find molecules which are killed to be safe in patients and prove that in the clinic.
• Design-Make-Test Cycle

  A) design

  B) synthesis

  C) testing

  D) analysis

  E) data

  
• what are Structure-Activity Relationships?

  Concept in drug discovery and development that clarifies thee relationship between the chemical structure of a molecule and its biological activity.
• what do SAR studies aim to understand?

  understand how specific structural features oof a molecule contribute to its pharmacological effects such as efficacy, potency, selectivity and toxicity
• the understanding of SARs is generally developed through what?

  A design-make-test-analyse cycle.
• what are peptic ulcers?

  localised erosions of mucous membranes of the stomach and/or duodenum
• what one thing aggravates/causes peptic ulcers?

  excessive gastric acid (HCl)
• what class of drugs are cimetidine and ranitidine?

  H2 antagonist/inverse agonist
• what is histamine?

  A biologically signalling molecule, involved in immune response neurotransmission and gastric acid release.
• Guanidine containing analogs of histamine exhibit partial agonism however they have very high pKa and so have very little neutral fraction at physiological pH and so very poor bioavailability
• 1st molecule - having the benzene ring with ester attached, makes the ring more of an electron-deficient ring as electrons are pulled away from the π system by the oxygen.

  2nd and 3rd molecule - attaching a methoxy on, the oxygen can donate its electrons into the ring system increasing electron density = help balance the efficacy and stability of compound.

  
• how omeprazole and related compounds form their active species:

  They are prodrugs that undergo a series of intramolecular reactions in the stomach to form the active 'sulfenamide' drug. Molecule reacts with itself in acidic environments to form an intermediate. The intermediate can go back and form the parent drug or It can rearrange to form a species.
• important thing to take from the mechanism of omeprazole...

  The mechanism is due to the acid-mediated rearrangement to form the active drug species in the stomach and it's driven by the electronics of the ring systems in the parent compound.
• mechanism of action of omeprazole - binding...

  The active drug irreversibly binds at the luminal opening of the H+/K+ ATPase on the parietal cells in the stomach and reacts with Cys813. This blocks the channel and prevents H+ transport therefore increasing gastric pH.
• How does the H+/K+ ATPase work?

  They bind ATP and use energy from the hydrolysis of ATP to pump H+ ions into the stomach.
• the potency of irreversible drugs comes from what?

  From reversible binding (K i) and irreversible reaction (K inact) steps, with the latter dominating for omeprazole and related compounds
• how does omeprazole have a long duration of action?

  The irreversible binding (forms a covalent bond) of the sulfenamide means omeprazole has a long duration of action – H+ efflux remains inhibited even after the drug is cleared from the body
• Despite the site of action being the stomach, omeprazole acts through systemic circulation and re-exposure to the stomach from the blood. Why is this?

  If we allow this to not happen and allow the drug to see the stomach acid in the first pass through, it rearranges two quickly and doesn’t reach the site of action and is so destroyed.
• how is omeprazole formulated to delay action in the first pass through the stomach?

  • Dosed as gastro-resistant tablets
  • for children - a suspension, dosed with a large amount of carbonate to neutralise the stomach pH with the absorption phase
• Omeprazole is used as a racemate as a result of the stereogenic centre on the sulphur.
• S-omeprazole is metabolized more slowly than R-omeprazole, resulting in reduced (first pass) clearance and higher total exposure than the racemate. So better efficacy.