Metabolism And Toxicology Flashcards
What makes a good lead compound
Good target interactions
Good PK
Good pharmaceutics
Novelty
Why is it important to have an understanding of met and tox?
To assess possible limitations to improve the properties of the drug
How can you improve drug characteristics?
Pro drug approach
Block metabolism
Improve delivery
Design out toxixity
What is a novel drug?
Innovative product that serves unmet medical needs or significantly helps advance patient care and public health.
What is an NME?
Have chemical structures which have never been approved before
What happens during Phase 1 of metabolism
mainly oxidation reactions, occurs in the liver by cyp450 mono-oxygenase enzymes
What happens during Phase 2 of metabolism
conjugation reactions- drugs are conjugated with water soluble groups to aid urinary and biliary excretions
Types of P1 metabolism
aromatic/aliphatic hydroxylation, N&O de-methylation, amide hydrolysis, epoxidation, ester hydrolysis, amine oxidation, nitro-reduction
What happens during epoxidation?
double bond is broken, oxygen group becomes attached to each carbon
What happens during amide hydrolysis
amide bond is hydrolysed, results in the formation of a carboxylic acid and an amine.
where is amide hydrolysis the fastest and slowest?
fastest in the liver, slower in the stomach
What happens during nitro reduction?
production of toxic intermediates (nitroso groups), by hepatic reductases
What are the types of oxidation reactions?
aliphatic and aromatic hydroxylation, epoxidation and N&O de-methylation
What is the most common reaction of phase 2 metabolism
Glucoronodation- glucoronic acid group is conjugated to drug to increase the solubility
what can occur during phase 2 metabolism
glucoronidation, sulphate conjugation and aromatic carboxylic acids conjugated with glycine
what happens during sulphate conjugation
sulphate group is added to N or O of a compound.
what happens during aromatic carboxylic acids conjugated with glycine
removal of OH group of carboxylic acid, addition of primary amide
what should be considered when anticipating Phase 2 reactions
polar conjugation could result in the drug being excreted too rapidly (reduce t1/2)
important not to block any important hydrogen bonding sites as this can lead to drug accumulation
What methods are used to predict toxicology
- Binding assays -wet screening (measures the interaction between two molecules)
- Off target in silico screening- virtual kinase library (screen similar drug candidates to infer off target effects)
- structural alerts (identify functional groups that are likely to cause toxicity)
- Metabolomics- Urine analysis (study of small molecules within cells, tissues and organs)
toxicology of- nitro-aromatics and anilines
- metabolised into Nitroso groups= toxic
- nitroso group reacts with proteins and nucleic acids to form covalent adducts
toxicology of- quinones
v toxic
very reactive to nucleophiles
(example= paracetamol toxicity- 15% is metabolised to quinones in the liver, this accumulates and causes liver damage)
toxicology of- alkyl halides
- I>B>F
- react with nucleophiles
- not aromatic halides
toxicology of- carboxylic acids
- metabolised to acetylglucuronides which are chemically stable
- these reach high concentrations in the plasma and undergo ester hydrolysis producing glucuronic acid whi h will irreversibly bind to proteins and nucleic acid
toxicology of- Michael Acceptors
react with nucleophiles and form adducts that detoxifies the michael acceptors
What is a bioisostere?
function group (s) of similar properties and shape
Bioisostere of H
F
C-F bond is stronger than C-H bond and cannot be broken easily
Bioisostere of CH3
CL
CL atom cannot be easily oxidised
Bioisostere of Nitro’s
Trifluro-methyl, cyanide and lactone (cyclic ester)
Bioisostere of Amines
Methyl and hydroxy
similar shapes but don’t mimic basicity
Bioisostere of COOH (ph~5)
tetrozole (Ph=4.9) and 2,4-diflurohenol(Ph= 6)
Tetrozole= better as similar shape and mimics acidity
