PHCY258 Introduction to Drug Action

L18 Lead Optimisation & Pharmacokinetics

Lecture 18: Dr Joel Tyndall

 Lead Optimisation

Learning Objectives - Lecture

• Understand the principles in optimising “access” to a drug target

• Describe characteristics of prodrugs

 Lead Optimisation
References

Patrick, G.L. (2009)

An Introduction to Medicinal Chemistry 4th Ed.
Oxford University Press;
Ch. 14
 Lead Optimisation
Drug Development
• Identify target disease
• Identify drug target
• Establish testing procedures
• Find a lead compound
• Structure Activity Relationships (SAR)
• Identify a pharmacophore
• Drug design - optimising target interactions

• Drug design - optimising pharmacokinetic properties

• Toxicological and safety tests

• Chemical development and production
• Patenting and regulatory affairs
• Clinical trials
 Lead Optimisation
Drug Development

• Improve pharmacokinetic properties

• Optimise chemical and metabolic stability

• Optimize hydrophilic / hydrophobic balance

• Optimize solubility

• Optimize drug half life

• Optimize distribution characteristics

 Optimising Access to Target
Optimising hydrophilic/hydrophobic properties

• Influence solubility

• Important for ADME

• “Absorption, Distribution, Metabolism, Excretion”

• Too polar (hydrophilic) cannot easily cross cell membranes in gut wall

• Can inject - cannot be used for intracellular targets

• Polar functional groups - plasma protein binding; Remove this

phase II conjugation and rapid excretion
 Optimising Access to Target
Optimising hydrophilic/hydrophobic properties

• Too hydrophobic

• orally – poor absorption - dissolved in fat globules in gut

• injected - poorly blood soluble - taken up by fat tissue
• Low circulating levels

• Hydrophobic character - partition coefficient (P)

Concentration of drug in octanol

P=
Concentration of drug in aqueous soln

• Hydrophobic drugs, high log P....

 Optimising Access to Target
Optimising hydrophilic/hydrophobic properties

• Variation of alkyl groups to alter polarity

• Too polar Mask a polar group, e.g. -OH → ether or ester

-COOH → ester, amide
• Prodrugs useful - see later

• Too hydrophobic Reduce the size or remove alkyl groups;

methylene shuffle
 Optimising Access to Target
Optimising hydrophilic/hydrophobic properties

• Variation of polar functional groups

• Add a polar group! ↑ polarity

• Decrease polarity .....

• But only if they are NOT required for activity
 Optimising Access to Target
Optimising hydrophilic/hydrophobic properties

• Variation of N-alkyl substituents to vary pKa

• pKa outside 6-9 are too strongly ionised - poor absorption across
membranes

• Alter pKa to bring it into range

• More alkyl groups (on N) ↑ steric bulk,
hinder solvation,
• Preventing stabiliation of the ion..... Balance!

• Reduce basicity
• Amidine - too basic for effective absorption
• Isoquinoline ↓ basicity ↑ absorption
 Optimising Access to Target
More resistant to chemical/enzymatic degradation

• Steric shields

• Esters and amides - problem - _____________

• Add a steric shield - hinders attack

• E.g. bulky alkyl group
 Optimising Access to Target
More resistant to chemical/enzymatic degradation

• Electronic effects of bioisosteres

Ester Carbamate
O
N Acetylcholine
O

O O
R R
O N
H
Ester Amide
 Optimising Access to Target
More resistant to chemical/enzymatic degradation

• Steric hindrance and electronic stabilisation combined:

• “stereoelectronic”

lignocaine
 Optimising Access to Target
More resistant to chemical/enzymatic degradation

• Metabolic blockers • Removal/replacement of metabolically

susceptible groups

• Susceptible to
oxidation

• Longer lasting
because ..........

• Can also replace CH3 with CF3, CHF2, CH2F

 Optimising Access to Target
More resistant to chemical/enzymatic degradation

•Removal/replacement of metabolically susceptible groups

• What if this group is important for binding?

• Mask group as a prodrug; or shift the vulnerability

OH OH
H
Noradrenaline HO NH2 HO N
Isoprenaline
Methylation via COMT HO HO

OH
H
N
Require both -OH groups for H-
Salbutamol HO
bonding to target receptor
HO
 Optimising Access to Target
Less resistance to drug metabolism (???????)

Stable (metabolism) drug - slow to be excreted - toxicity - lingering side effects

Introduce metabolically susceptible group - shortens half life

 Optimising Access to Target
Targeting Drugs

• Targeting the exact location - tumour cells

• E.g. using molecular transporters - amino acid
• Tumours grow much more rapidly

• Targeting GI infections
• Not absorbed (How?)

• Targeting peripheral regions (not CNS)

• Increased polarity reduces the ability to cross Blood-Brain Barrier
 Optimising Access to Target
Reducing Toxicity

• Drug “candidates” often fail clinical trials due to toxic side effects
• Metabolites? Build in resistance to metabolism

• Particular functional groups responsible for toxic metabolites

• E.g. Aromatic nitro groups, Aromatic amines, polyhalogenated
groups are often metabolised to toxic products

• Can vary apparently harmless substituents

http://www.youtube.com/watch?v=4Zv9vRz4QYM
 Optimising Access to Target
Prodrugs

“Compounds which are inactive but can be converted to an active

form in the body (metabolised in vivo)”

• Usually activated by an enzyme

• Useful for acid sensitivity, poor membrane permeability,

drug toxicity, bad taste and short duration of action

Enalapril O N
N
H OH
O O
O
 Optimising Access to Target
Prodrugs

• Uses:
• Improving membrane permeability

• Prolonging activity

• Masking toxicity and side effects

• Varying water solubility

• Drug targeting

• Improving chemical stability

 Prodrugs
Improve membrane permeability

• Esters – can mask a carboxylate group in order to cross membrane

• Less polar – can cross cell membranes
• hydrolysed by esterases in blood
• Introducing an EWG (-OCH2CF3) easier to hydrolyse

• N-methylation (liver)
• Reduce polarity – improving membrane permeability

• Trojan horse – taking advantage of transport proteins

 Prodrugs
Prolong Activity

• Prodrugs
• Slow conversion to active form

• Diazepam

• To maintain a sustained drug level add very lipophilic group

• Drug will be stored in fat tissue – lipophilic group removed slowly
• Drug slowly and steadily released
 Prodrugs
Mask drug toxicity and Side effects

• Salicylic acid - analgesic (pain killer) - cause gastric bleeding (phenol)

• Mask the phenol as an ester

O OH O OH

OH O

Salicylic Acid

• Aspirin is a prodrug (Does salicylate inhibit COX?)

• Prodrugs can target micro-organisms i.e. be activated by viral or

parasitic enzymes
 Prodrugs
Alter water solubility

• Lower solubility
• Bad taste, lowering water solubility avoids tongue!
• Chloramphenicol palmitate ester (quickly hydrolysed)

OH OH OH O (CH2)14CH3

Cl Cl
HN HN
O2N Cl O2N Cl
O O

• Improve solubility
• Good for IV (higher conc, smaller volumes)
• Chloramphenicol succinate O
OH
OH O
O
Cl
HN
O2N Cl
O
 Prodrugs
Targeting of drugs

Methanamine, stable above pH 5

• More acid pH, spontaneously degrades to generate formaldehyde

• antibacterial properties (UTI)
• Normal blood pH 7.4
• Once excreted into infected urinary tract (acidic pH due to infection)
 Prodrugs
Chemical stability

• Ampicillin decomposes in conc. aqueous solution due to intramolecular

nucleophilic attack on the lactam ring

• Hetacillin “locks away” the nitrogen

• Hetacillin slowly decomposes after administration

 Lead Optimisation
Optimising Access to the Drug Target

• Summary

• Optimising hydrophilic/hydrophobic properties

• Avoiding to chemical/enzymatic degradation

• Less resistance to drug metabolism (?why)

• Targeting drugs

• Reducing Toxicity
 Lead Optimisation
Characteristics of Prodrugs

• Summary

• Increase membrane permeability

• Prolong activity

• Mask toxicity and side effects

• Alter water solubility

• Targeting of drugs

• Chemical stability