Lead optimisation in drug design Flashcards
What permeability does a drug have to have to work efficiently?
solubility and membrane permeability
What effect will varying alkyl substituents have on solubility and membrane permeability ?
Vary size of alkyl groups to vary the hydrophilic/lipophilic balance of the structure
LARGER alkyl groups INCREASE lipophilicity (logP): enhance membrane permeability by passive diffusion
Often feasible to remove alkyl groups from heteroatoms and replace with different alkyl groups
What effect will masking or removing polar groups have on solubility and membrane permeability?
Alcohol, amine and COOH = all polar, hydrophilic
If they weren’t good at getting through membranes – add something to make more lipophilic
Hydrophilic = low log P
What effect will adding polar groups have on solubility and membrane permeability?
On the other hand, if not polar enough, you can add a polar group which increases polarity, hydrophilic character, increasing water SOLUBILITY
THE BIGGER THE ATOM THE MORE LIPOPHILLIC IT IS
*fluorine often blocks metabolism – blocking site that can be metabolised by liver enzymes
What effect will varying pKa have on solubility and membrane permeability?
Varying pKa alters percentage of drug which is ionised
Alter pKa to obtain required ratio of ionised to unionised drug
Vary alkyl substituents on amine nitrogens
Vary aryl substituents to influence aromatic amines or aromatic carboxylic acids
What can be introduced to block esters hydrolysing to COOH and alcohol ?
Introduce bulky group as a shield.
Protects a susceptible functional group (e.g. ester, amide) from hydrolysis
Hinders attack by nucleophiles or enzymes
Used to increase chemical and metabolic stability.
What do steric shields do?
Steric shield PROTECTS molecule (tertiary butyl) – occupies a large space and BLOCKS hydrolysis of terminal amide – giving more stability as it can fit into enzyme active site
Electronic shielding of NH2 - what is it used for?
Used to stabilise labile functional groups (e.g. esters).
Replace labile ester with more stable carbamate or amide.
Nitrogen feeds electrons into carbonyl group and makes it less reactive.
Increases chemical and metabolic stability.
What are the stereoelectronic effects?
Steric and electronic effects used in combination
Increases chemical and metabolic stability
What are some features of procaine?
local anaesthetic
ester
susceptible to esterases
short duration
What are some features of lidocaine? Why does it have a longer duration?
Contains Ortho-methyl groups that act as steric shields - bulky groups get in the way of hydrolysis (para position would be ineffective)
Hinder hydrolysis by esterases
Amide more stable than ester (electronic effect) : RESONANCE
What are metabolic blockers?
Metabolism of drugs usually occurs at specific sites
Introduce groups at a susceptible site to block the reaction.
Increases metabolic stability and drug lifetime (half life)
Attach group at site so it doesn’t get oxidised (CH3 methyl group) = LONGER LIFETIME
What does removing/replacing susceptible metabolic groups do?
Remove susceptible group or replace it with a metabolically stable group e.g. modification of tolbutamide (Type II Diabetes)
replace groups to block metabolism = ends up with LONGER half life as not excreted as quickly
What does shifting susceptible metabolic groups do?
Used if the metabolically susceptible group is important for binding.
Shift its position to make it unrecognisable to metabolic enzyme.
Must still be recognised by the target.
Too rapidly hydrolysed
What is introducing chemically susceptible groups used for?
Used to DECREASE drug lifetime
Avoids reliance on metabolic enzymes and individual variations
Example of a chemically susceptible group?
Atracurium - i.v. neuromuscular blocking agent
Stable at acid pH, unstable at blood pH (slightly alkaline).
Self destructs by Hoffmann elimination and has short lifetime.
Allows anaesthetist to control dose levels accurately.
Quick recovery times after surgery
Molecule needs to ‘fall apart’
What is Hoffmann elimination?
is a process where a quaternary ammonium reacts to create a tertiary amine and an alkene by treatment with excess methyl iodide followed by treatment with silver oxide, water, and heat.
Atracurium, a nondepolarizing muscle relaxant, is eliminated through several pathways, including Hofmann elimination (spontaneous degradation in plasma and tissue at normal body pH and temperature) and ester hydrolysis (catalysis by nonspecific esterases).
What is a prodrug?
inactive compounds which are converted to active compounds in the body
What are the uses of prodrugs?
- To improve membrane permeability
- To prolong activity
- To mask toxicity and side effects
- To lower water solubility
- To increase water solubility
- To use to target drugs
What are used to improve membrane permeability?
ESTERS - used to mask polar and ionisable COOHs.
Hydrolysed in blood by esterases
Used when a COOH is required for target binding
Leaving group (alcohol) should ideally be non-toxic
What is enalapril?
Prodrug for enalaprilate (antihypertensive)
Ethanol is formed from ethyl ester (very small amount)
Ethanol is better than methanol as methanol can be oxidised to formaldehyde which can cause blindness (ethanol is antidote)
What is the trojan horse strategy?
mimics something natural in body that is normally carried across membranes via active transport
Prodrug designed to mimic biosynthetic building block
Transported across cell membranes by carrier proteins
What is levodopa?
Prodrug for dopamine - parkinsons (neurotransmitter)
More polar amino acid
Carried across cell membranes by carrier proteins for amino acids
Mimics tyrosine
Decarboxylated in cell to dopamine
Dopamine is too polar to cross cell membranes and BBB
Why would you want to prolong activity?
reduces rate of excretion
How would you prolong activity ?
mask polar group to prolong half life
Example of prodrug that prolongs activity ?
Azathioprine (immunosupressant prodrug used to prevent rejection in organ transplants and/or for the treatment of autoimmune diseases e.g. rheumatoid arthritis and Crohns) for 6-mercaptopurine
How does azathioprine work?
Slow conversion to 6-mercaptopurine via non-enzymatic reduction
longer lifetime
What is another example for prolonged activity prodrug?
Diazepam for nordazepam
- add hydrophobic groups
What are hydrophobic esters of fluphenazine used for?
(anti-psychotic) given by i.m. injection concentrated in fatty tissue slowly released into the blood supply rapidly hydrolysed in the blood -- cleaves ester to give drug
When is masking toxicity and side effects used?
when groups are important for activity
What is marked in salicylic acid and what effects does it have?
Phenol group on salicylic acid causes stomach ulcers - phenol is masked by ester in aspirin and is hydrolysed by esterases in the bloodstream
what is the prodrug for phosphoramide mustard? (alkylating agent)
Cyclophosphoramide (non toxic, orally active)
What does first phosphorylation require for antiviral drugs?
viral thymidine kinase
Only activated in virally infected cells
Non-toxic to uninfected cells
When are prodrugs to lower water solubility used ?
Used to reduce solubility of foul tasting orally active drugs
Less soluble on tongue
Less revolting taste
Increase hydrophobicity
Example of prodrug to reduce water solubility ?
Palmitate ester of chloramphenicol
What prodrug is used to INCREASE water solubility?
Phosphate ester of clindamycin
- more soluble in water
- less painful on injection
What prodrug is used to target drugs?
Hexamine (methenamine)
Stable and inactive at pH>5
Stable at blood pH
Used for urinary infections where pH<5 because it decomposes in acid
Degrades at pH<5 to form formaldehyde (antibacterial agent)
