L32/33 - Chemical Basis for Drug Degradation

• What's the mechanism for base hydrolysis of an ester?

  
  

  What are the products?

  carboxylate ion and alcohol.

  
• What's the mechanism for acid hydrolysis of an ester?

  
  

  What are the products?

  carboxylic acid, alcohol and acid catalyst

  
• What is drug degradation commonly due to?

  Photolytic Degradation or hydrolysis.
• Why are reactive functional groups eg acyl chlorides not commonly found in drugs?

  Bc they are electrophilic, so react with nucleophiles (body is nucleophilic) and are toxic.
• What is photolytic Degradation?

  
  

  How does it occur?

  Degradation by light - usually by oxidation or benzyllic oxidation.

  
  

  1) Molecule absorbs a photon from IR, visible light or UV.

  
  

  2) moves from ground to excited state.

  
  

  3) Can then spontaneously decompose or react.
• Give an example of some medicines that photolytic degradation can occur to.

  - Chloramphenicol eyedrops (likely to be exposed to light).

  
  

  - corticosteroids and antimycotics (antifungals) can degrade by up to 50% when exposed to light after application

  
• What products cause the most problems with photolytic degradation?

  
  

  How can we avoid the degradation?

  - Extemporaneously dispensed products.

  
  

  - Avoid by using amber bottles, blister packs etc.

  - Use additives or physical quenchers.
• What do physical quenchers do?

  cause physical delay of excited state before decomposition occurs
• What's an advantage to photolytic degradation?

  Can reduce effects of pharmaceutical waste on environment.
• What groups are prone to hydrolytic degradation?

  esters and amides, lactones and lactams (cyclic esters and cyclic amides).

  
• Give an example of a medicine susceptible to hydrolytic degradation.

  Penicillin suspension - kept in fridge after reconstitution to minimise hydrolysis of strained lactam ring.

  
  

  Many beta-lactam drugs are not suited to IV bc of this reactivity.

  
• What's the issue with changing a medication's packaging, eg through blister boxes?

  Can invalidate manufacturer's warranty and hange stability

  
• What are the complications of chemical degradation of biologics?

  Large size/Mw, complicated structure, backbone hydrolysis.

  
  

  Oxidation of susceptible side chains eg Cys and Met.
• Eg, what can happen if 2x Cys residues are oxidised?

  Form a disulphide bond, which can result in protein aggregation.
• What are some pharmacological properties which must be considered in modern drug design?

  - Selectivity of the drug to the target, to minimise ADRs.

  
  

  - Potency at biological target, to achieve a sensible dose.

  
• What does good drug design encompass?

  combining pharmacological properties with drug-like properties.
• In exam q's, typically we need to...

  - identify ligand-receptor interactions.

  
  

  - suggest amino acids/groups that would increase beneficial interactions.

  
  

  - decide whether an amino acid is charged at physiological pH.

  
• What does good drug design rely on?

  - Good molecular complementarity (size, nature of groups).

  
  

  - Good interactions between ligand and target.

  
  

  - Good drug like properties.
• What are good drug-like properties?

  - Lipinski's Rule of 5.

  
  

  - Metabolic/chemical stability.

  
  

  - Good drug-like properties translate to good ADME/toxicity characteristics.
• Example: Suvorexant!

  
  

  What's it used for?

  
  

  What's a tolyl group?

  - insomnia treatment.

  
  

  - Tolyl = methyl attached to aromatic ring.

  
  

  1) molecule discovered through high throughput screening.

  
  

  2) BUT low bioavailability (hepatic first pass). Metabolic instability due to oxidation of tolyl group.

  
  

  3) Had to edit again to increase bioavailability.