Lead optimisation in drug design

Question 1

What permeability does a drug have to have to work efficiently?

Answer 1

solubility and membrane permeability

Question 2

What effect will varying alkyl substituents have on solubility and membrane permeability ?

Answer 2

 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

Question 3

What effect will masking or removing polar groups have on solubility and membrane permeability?

Answer 3

 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

Question 4

What effect will adding polar groups have on solubility and membrane permeability?

Answer 4

 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

Question 5

What effect will varying pKa have on solubility and membrane permeability?

Answer 5

 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

Question 6

What can be introduced to block esters hydrolysing to COOH and alcohol ?

Answer 6

 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.

Question 7

What do steric shields do?

Answer 7

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

Question 8

Electronic shielding of NH2 - what is it used for?

Answer 8

 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.

Question 9

What are the stereoelectronic effects?

Answer 9

 Steric and electronic effects used in combination

 Increases chemical and metabolic stability

Question 10

What are some features of procaine?

Answer 10

local anaesthetic
ester
susceptible to esterases
short duration

Question 11

What are some features of lidocaine? Why does it have a longer duration?

Answer 11

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

Question 12

What are metabolic blockers?

Answer 12

 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

Question 13

What does removing/replacing susceptible metabolic groups do?

Answer 13

 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

Question 14

What does shifting susceptible metabolic groups do?

Answer 14

 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

Question 15

What is introducing chemically susceptible groups used for?

Answer 15

Used to DECREASE drug lifetime

Avoids reliance on metabolic enzymes and individual variations

Question 16

Example of a chemically susceptible group?

Answer 16

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’

Question 17

What is Hoffmann elimination?

Answer 17

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).

Question 18

What is a prodrug?

Answer 18

inactive compounds which are converted to active compounds in the body

Question 19

What are the uses of prodrugs?

Answer 19

• 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

Question 20

What are used to improve membrane permeability?

Answer 20

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

Question 21

What is enalapril?

Answer 21

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)

Question 22

What is the trojan horse strategy?

Answer 22

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

Question 23

What is levodopa?

Answer 23

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

Question 24

Why would you want to prolong activity?

Answer 24

reduces rate of excretion

Question 25

How would you prolong activity ?

Answer 25

mask polar group to prolong half life

Question 26

Example of prodrug that prolongs activity ?

Answer 26

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

Question 27

How does azathioprine work?

Answer 27

Slow conversion to 6-mercaptopurine via non-enzymatic reduction
longer lifetime

Question 28

What is another example for prolonged activity prodrug?

Answer 28

Diazepam for nordazepam

- add hydrophobic groups

Question 29

What are hydrophobic esters of fluphenazine used for?

Answer 29

(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

Question 30

When is masking toxicity and side effects used?

Answer 30

when groups are important for activity

Question 31

What is marked in salicylic acid and what effects does it have?

Answer 31

Phenol group on salicylic acid causes stomach ulcers - phenol is masked by ester in aspirin and is hydrolysed by esterases in the bloodstream

Question 32

what is the prodrug for phosphoramide mustard? (alkylating agent)

Answer 32

Cyclophosphoramide (non toxic, orally active)

Question 33

What does first phosphorylation require for antiviral drugs?

Answer 33

viral thymidine kinase
 Only activated in virally infected cells

 Non-toxic to uninfected cells

Question 34

When are prodrugs to lower water solubility used ?

Answer 34

 Used to reduce solubility of foul tasting orally active drugs
 Less soluble on tongue
 Less revolting taste
 Increase hydrophobicity

Question 35

Example of prodrug to reduce water solubility ?

Answer 35

Palmitate ester of chloramphenicol

Question 36

What prodrug is used to INCREASE water solubility?

Answer 36

Phosphate ester of clindamycin

• more soluble in water
• less painful on injection

Question 37

What prodrug is used to target drugs?

Answer 37

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)