Chapter 14 Pharmacokinetics
Getting a drug to the target in the
body
DRUG DESIGN AND DEVELOPMENT
Stages
1) Identify target disease
2) Identify drug target
3) Establish testing procedures
4) Find a lead compound
5) Structure Activity Relationships (SAR)
6) Identify a pharmacophore
7) Drug design- optimizing target interactions
8) Drug design - optimizing pharmacokinetic properties
9) Toxicological and safety tests
10) Chemical development and production
11) Patenting and regulatory affairs
12) Clinical trials
PHARMACOKINETICS - DRUG DESIGN
Aims
•To improve pharmacokinetic properties of lead compound
•To optimize chemical and metabolic stability
•To optimize hydrophilic / hydrophobic balance
•To optimize solubility
•To optimize drug half life
•To optimize distribution characteristics
PHARMACOKINETICS - DRUG DESIGN
Notes
•Drugs must be sufficiently polar to be soluble in aqueous conditions
•Drugs must be sufficiently polar to interact with molecular targets
•Drugs must be sufficiently ‘fatty’ to cross cell membranes
•Drugs must be sufficiently ‘fatty’ to avoid rapid excretion
•Drugs must have both hydrophilic and lipophilic characteristics
•Many drugs are weak bases with pKa’s 6-8
+H
N
H
N
H
H
-H
Crosses
membranes
Receptor interaction
& water solubility
Solubility and membrane permeability
Vary alkyl substituents
Rationale
•Varying the size of alkyl groups varies the hydrophilic / hydrophobic balance of the
structure
•Larger alkyl groups increase hydrophobicity
Disadvantage
May interfere with target binding for steric reasons
Methods
•Often feasible to remove alkyl groups from heteroatoms and replace with different
alkyl groups
•Usually difficult to remove alkyl groups from the carbon skeleton - full synthesis
often required
Solubility and membrane permeability
Vary alkyl substituents
Methylene shuffle
CH3
O
O
CH3
N
HN
N
Extra bulk
CH3
O
O
O S
O
CH3
O
N
O
CH3
O S
O
N
N
HN
N
N
N
N
N
HN
N
CH3
N
N
CH3
Methylene
shuffle
H3C
O S
N
N
N
N
Viagra
CH3
•Second-generation
anti-impotence agent
•Increased selectivity
•Excess lipophilicity
O
UK343664
H3C
Reduced lipophilicity
Better in vivo activity
Solubility and membrane permeability
‘Masking’ or removing polar groups
Rationale
Masking or removing polar groups decreases polarity and increases
hydrophobic character
Disadvantages
•Polar group may be involved in target binding
•Unnecessary polar groups are likely to have been removed already (simplification
strategy)
•See also prodrugs
CH3I
Methods
R
R
OH
H
N
CH3COCl
R
NHR
OMe
CH3
R
O
R
OH
C
O
H+ / R'OH
R
OR'
C
O
Solubility and membrane permeability
Adding polar groups
Rationale
•Adding polar groups increases polarity and decreases hydrophobic character
•Useful for targeting drugs vs. gut infections
•Useful for reducing CNS side effects
Cl
N
N
N
S
H
C
N
N
N
N
OH
N
C
O
F
Cl
Cl
Tioconazole
Antifungal agent with poor
solubility - skin infections only
Disadvantage of adding polar groups
May introduce unwanted side effects
F
Fluconazole
Systemic antifungal agent
improved blood solubility
Solubility and membrane permeability
Vary pKa
Rationale
•Varying pKa alters percentage of drug which is ionised
•Alter pKa to obtain required ratio of ionised to unionised drug
Method
•Vary alkyl substituents on amine nitrogens
•Vary aryl substituents to influence aromatic amines or aromatic carboxylic acids
Disadvantage
•May affect binding interactions
Solubility and membrane permeability
Vary pKa
N
O
N
N
H
H2N
NH
N
O
N
N
H
O
(I)
N
N
NH2
N
O
PRO3112
amidine
Antithrombotic
Too basic
Decreased basicity
Nitrogen locked into heterocyclic ring
Drug stability
Steric Shields
Rationale :
•Used to increase chemical and metabolic stability
•Introduce bulky group as a shield
•Protects a susceptible functional group (e.g. ester) from hydrolysis
•Hinders attack by nucleophiles or enzymes
O
Antirheumatic agent
D1927
H
N
HS
CONHMe
N
H
Terminal amide
O
C
O
N
H3C
O
CH3
CH3
Steric
shield
Blocks hydrolysis of
terminal amide
Drug stability
‘Electronic shielding’ of NH2
Rationale
•Used to stabilise labile functional groups (e.g. esters)
•Replace labile ester with more stable urethane or amide
•Nitrogen feeds electrons into carbonyl group and makes it less reactive
•Increases chemical and metabolic stability
O
O
C
H3C
R
O
C
H2N
R
O
ISOSTERE
O
O
C
H3C
C
R
O
CH3
ISOSTERE
R
NH
Drug stability
‘Electronic shielding’ of NH2
O
O
R
N
H
R
C
R'
N
H
C
R'
Drug stability
Stereoelectronic Effects
Rationale
•Steric and electronic effects used in combination
•Increases chemical and metabolic stability
H2N
Lidocaine
CH3
O
O
C
O
CH2CH2NEt2
Procaine
N
H
C
CH2NEt2
CH3
•Local anaesthetic
•Susceptible to esterases
•Short duration
•ortho Methyl groups act as steric shields
•Hinder hydrolysis by esterases
•Amide more stable than ester (electronic
effect)
Drug stability
Bio-isosteres
Rationale
•Replace susceptible group with a different group without affecting activity
•Bio-isostere shows improved pharmacokinetic properties
•Bio-isosteres are not necessarily isosteres
Examples
•Amides and urethanes for esters (see earlier)
•Du122290 (dopamine antagonist)
NEt
NEt
O
OMe
OMe
EtSO2
Sultopride
Pyrrole ring =
bioisostere for amide
NH
NH
EtSO2
Du122290
Drug stability
Metabolic blockers
Rationale:
•Metabolism of drugs usually occurs at specific sites.
•Introduce groups at a susceptible site to block the reaction
•Increases metabolic stability and drug lifetime
Me
O
C
Me
Me
O
Me
O
C
Me
O
Me
O
6
Me
H
Megestrol
Acetate
•Oral contraceptive
•Limited lifetime
C
H
H
O
H
6
Me
Metabolic
Oxidation
O
O
H
H
Me
C
Me tabolism
Blocke d
Drug stability
Remove / replace susceptible metabolic groups
Rationale
•Remove susceptible group or replace it with a metabolically stable group e.g.
modification of tolbutamide (antibiotic)
Susceptible
group
Me
O
S NH C NH CH2CH2CH2CH3
O
O
Unsusceptible
group
Cl
O
S NH C NH CH2CH2CH3
O
O
TOLBUTAMIDE
Metabolism
HOOC
O
S NH C NH CH2CH2CH2CH3
O
O
Rapidly excreted - short lifetime
Metabolism
Drug stability
Shifting susceptible metabolic groups
Rationale
•Used if the metabolically susceptible group is important for binding
•Shift its position to make it unrecognisable to metabolic enzyme
•Must still be recognisable to target
Unsusceptible
group
e.g. Salbutamol
OH
Susceptible
group
HO
OH
HO
Shift
Group
Me
CHCH2
NH
C
Me
Me
OH
Me
NH
C
Me
Me
Inactive
C
CH2
Me
NH C
Catechol
O-Methyl
Trans feras e
MeO
CHCH2
HO
OH
Salbutamol
Catechol
O-Methyl
Transferase
HO
H
Me
Me
Drug stability
Introducing susceptible metabolic groups
Rationale
•Used to decrease metabolic stability and drug lifetime
•Used for drugs which ‘linger’ too long in the body and cause side effects
•Add groups known to be susceptible to Phase I or Phase II metabolic reactions
Examples Anti-arthritic agents
SO2Me
SO2Me
Cl
Cl
CH2OH
N
L787257
N
N
Resistant to metabolism
Excessively long half life
L791456
N
CH3
Metabolically
susceptible
CO2H
Drug stability
Introducing susceptible metabolic groups
Examples Anti-asthmatic agents
O
N
NC
O
OH
4 3
Me
O
Me
Cromakalim
N N
O
N
4 3
Me
O
Me
N
CO2Et
Me
N
N
OH
Me
N
O
HO
SO2
OH
Me
l abi le
O
UK143220
Me
UK157147
labi le
Notes
•Cromakalim produces cardiovascular side effects if it reaches the blood supply
•Add metabolic instability such that compound is rapidly metabolised in blood
•UK143220 - ester is quickly hydrolysed by esterases to an inactive acid
•UK 157147- phenol is quickly conjugated and eliminated
O
Drug stability
Introducing chemically susceptible groups
Rationale
•Used to decrease drug lifetime
•Avoids reliance on metabolic enzymes and individual variations
Example Atracurium - i.v. neuromuscular blocking agent
MeO
Me
MeO
N
O
O
C
C
CH2 CH2
OMe
OMe
O
(CH2)5 O
OMe
H
CH2 CH2
N
MeO
OMe
Notes
•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
OMe
Drug stability
Introducing chemically susceptible groups
Hoffmann
Elimination
Me
R
N
Me
-H
N
CH2 CH C
H
Ph
ACTIVE
R
H2C CH
O
Ph
INACTIVE
C
O
Drug Targeting
Linking a biosynthetic building block
Rationale:
•Drug ‘smuggled’ into cell by carrier proteins for natural building block (e.g. amino
acids or nucleic acid bases)
•Increases selectivity of drugs to target cells and reduces toxicity to other cells
Example Anticancer drugs
Cl
Cl
O
H3C
N
N
HN
Cl
Cl
O
Non selective alkylating agent
Toxic
H
N
Uracil Mustard
Notes:
•Alkylating group is attached to a nucleic acid base
•Cancer cells grow faster than normal cells and have a greater demand for
nucleic acid bases
•Drug is concentrated in cancer cells - Trojan horse tactic
Drug Targeting
Linking drugs to monoclonal antibodies
Rationale
•Useful for targeting drugs to cancer cells
•Identify an antigen which is overexpressed on a cancer cell
•Clone a monoclonal antibody for the antigen
•Attach a drug or poison (e.g. ricin) to the monoclonal antibody
•Antibody carries the drug to the cancer cell
•Drug is released at the cancer cell
Drug Targeting
Targeting gut infections
Rationale
•Design the antibacterial agent to be highly polar or ionised
•Agent will be too polar to cross the gut wall
•Agent will be concentrated at the site of infection
•Example - highly ionised sulfonamides
Drug Targeting
Targeting peripheral regions over CNS
Rationale
•Increase polarity of the drug
•Drug is less likely to cross the blood brain barrier
Reducing drug toxicity
Rationale
•Toxicity is often due to specific functional groups
•Remove or replace functional groups known to be toxic e.g.
•aromatic nitro groups
•aromatic amines
•bromoarenes
•hydrazines
•polyhalogenated groups
•hydroxylamines
•Vary substituents
•Vary position of substituents
Reducing drug toxicity
Varying substituents
•Fluconazole (Diflucan) - antifungal agent
N
N
N
N
N
OH
N
C
N
N
N
N
N
OH
N
C
F
Cl
Cl
UK-47265
F
Fluconazole
Substituents varied
Less toxic
Reducing drug toxicity
Varying substituent position
•Dopamine antagonists
H
N
NC
N
HN
H
N
O
N
HN
O
NC
Inhibits P450 enzymes
No inhibition of P450 enzymes
Prodrugs
Definition
Inactive compounds which are converted to active compounds in the body
Uses
•Improving membrane permeability
•Prolonging activity
•Masking toxicity and side effects
•Varying water solubility
•Drug targeting
•Improving chemical stability
•‘Sleeping agents’
Prodrugs to improve membrane permeability
Esters
•Used to mask polar and ionisable carboxylic acids
•Hydrolysed in blood by esterases
•Used when a carboxylic acid is required for target binding
•Leaving group (alcohol) should ideally be non toxic
Examples
Enalapril for enalaprilate (antihypertensive)
CH3
RO
O
N
H
N
O
CO2H
R=Et Enalapril
R=H Enalaprilit
Prodrugs to improve membrane permeability
Examples
Candoxatril for Candoxatrilat (protease inhibitor)
OMe
OMe
O
O
H
N
HO
O
O
Candoxatrilat
H
N
O
O
CO2H
O
Candoxatril
5-indanyl group
Notes
•Varying the ester varies the rate of hydrolysis
•Electron withdrawing groups increase rate of hydrolysis (e.g. 5-indanyl)
•Leaving group (5-indanol) is non toxic
CO2H
Prodrugs to improve membrane permeability
N-Methylation of amines
•Used to reduce polarity of amines
•Demethylated in liver
Examples - Hexobarbitone
O
Me
N
O
NH
O
Me
Prodrugs to improve membrane permeability
Trojan Horse Strategy
•Prodrug designed to mimic biosynthetic building block
•Transported across cell membranes by carrier proteins
Example -Levodopa for dopamine
HO
CH2
HO
CH2
HO
NH2
Dopamine
•Useful in treating Parkinson’s Disease
•Too polar to cross cell membranes and BBB
CH2
CO2H
C
HO
H
NH2
Levodopa
•More polar amino acid
•Carried across cell membranes by carrier
proteins for amino acids
•Decarboxylated in cell to dopamine
Prodrugs to improve membrane permeability
Blood
supply
H2N
Brain
cells
H2N
COOH
COOH
Enzyme
L-Dopa
H2N
Dopamine
BLOOD BRAIN
BARRIER
Prodrugs to prolong activity
Mask polar groups
Reduces rate of excretion
Example: Azathioprine for 6-mercaptopurine
O2N
N
SH
S
N
Me
N
N
N
N
N
N
H
6-Mercaptopurine
Suppresses immune response
Short lifetime
Eliminated too quickly
N
H
N
Azathioprine
Slow conversion to 6-mercaptopurine
Longer lifetime
Prodrugs to prolong activity
Example: Valium for nordazepam
H
Me
O
O
N
N
N
Cl
Valium
N-Demethylation
Cl
N
Nordazepam
Prodrugs to prolong activity
Add hydrophobic groups
•Drug concentrated in fat tissue
•Slow removal of hydrophobic group
•Slow release into blood supply
Example: cycloguanil pamoate (antimalarial)
CO2
Cl
NH3
N
OH
CH2
N
Me
OH
H3N
N
Me
CO2
Cycloguanil
Pamoate
Lipophilic
Prodrugs to prolong activity
Add hydrophobic groups
Example: Hydrophobic esters of fluphenazine (antipsychotic)
fatty ester
N
N
(CH2)8CH3
O
O
H
N
CF3
S
•Given by intramuscular injection
•Concentrated in fatty tissue
•Slowly released into the blood supply
•Rapidly hydrolysed in the blood supply
Prodrugs to mask toxicity and side effects
•Mask groups responsible for toxicity/side effects
•Used when groups are important for activity
Example: Aspirin for salicylic acid
O
OH
CO2H
H3C
O
CO2H
Salicylic acid
•Analgesic
•Causes stomach ulcers
•Due to phenol group
Aspirin
•Phenol masked by ester
•Hydrolysed by esterases
in bloodstream
Prodrugs to mask toxicity and side effects
Example:Cyclophosphoramide for phosphoramide mustard (anticancer agent)
NH
O
Phosphoramidase
Cl
(liver)
H2N
HO
N
Cyclophosphoramide
Non toxic
Orally active
Cl
Cl
P
P
O
O
N
Phosphoramide mustard
Alkylating agent
Cl
Prodrugs to mask toxicity and side effects
Example: Antiviral drugs
N
HO
N
N
N
N
PO
Vi ral
NH2 thymidi ne
kinase
Penciclovir
OH
N
N
N
N
NH2
P P PO
N
Cell kinases
OH
Notes
•First phosphorylation requires viral thymidine kinase
•Only activated in virally infected cells
•Non-toxic to uninfected cells
OH
N
N
NH2
Prodrugs to mask toxicity and side effects
LDZ for diazepam
Ar
O
CH3
O
H
N
N
H
NH2
a) Aminopeptidase
b) Cyclisation
Ar
N
O
N
O
Cl
CH3
Cl
LDZ
Diazepam
NH2
Avoids drowsy side effects of diazepam
Prodrugs to mask toxicity and side effects
Mechanism of activation
Ar
O
CH3
N
O
Cl
O
N
H
H
H
H
Ar
NH2
Enz
O
-H
N
-lysine
O
N
CH3
O
Cl
LDZ
CH3 NH2
N
Ar
HO
Cl
NH2
H
H 2O
Ar
+H
H
N
O
Ar
N
O
N
CH3
Cl
N
Ar
-H
N
O
N
CH3
CH3
Cl
Cl
Diazepam
Prodrugs to lower water solubility
•Used to reduce solubility of foul tasting orally active drugs
•Less soluble on tongue
•Less revolting taste
Example: Palmitate ester of chloramphenicol (antibiotic)
Palmitate ester
OH
H H
N
O
O
H H
N
H
O2N
O
OH
Cl
Cl
Cl
Esterase
H
O
OH
O2N
Chloramphenicol
Cl
Prodrugs to increase water solubility
•Often used for i.v. drugs
•Allows higher concentration and smaller dose volume
•May decrease pain at site of injection
Example: Succinate ester of chloramphenicol (antibiotic)
HO
O
Succinate ester
OH
H H
N
O
O
H H
N
H
O2N
O
OH
Cl
Cl
Cl
Esterase
H
O
OH
O2N
Chloramphenicol
Cl
Prodrugs to increase water solubility
Example: Phosphate ester of clindamycin (antibacterial)
CH3CH2CH2
Me
N
H
H
O
C
Cl
H
H
C
CH3
N C
H
O H
HO
OH H
H
SCH3
H
OPO32-
Less painful on injection
Prodrugs to increase water solubility
Example: Lysine ester of oestrone
Me
H
NH2
H
O
H
H
H
H2N
O
O
Prodrug
Me
H2N
H
NH2
H
H
+
O
OH HO
Lysine
Notes:
•Lysine ester of oestrone is better absorbed orally than oestrone
•Increased water solubility prevents formation of fat globules in gut
•Better interaction with the gut wall
•Hydrolysis in blood releases oestrone and a non toxic amino acid
O
Oestrone
Prodrugs used to target drugs
Example: Hexamine
N
N
N
N
Notes:
•Stable and inactive at pH>5
•Stable at blood pH
•Used for urinary infections where pH<5
•Degrades at pH<5 to form formaldehyde (antibacterial agent)
Prodrugs to increase chemical stability
Example: Hetacillin for ampicillin
Ph
O
Ph
O
Ampicillin
HN
'Locked'
Nitrogen
H3C
N
S
CH3
CH3
H2N
HN
S
CH3
N
O
CH3
N
O
O
OH
Hetacillin
CH3
O
H3C
CH3
OH
O
Notes:
•Ampicillin is chemically unstable in solution due to the a-NH2 group attacking
the b-lactam ring
•Nitrogen atom in heteracillin is locked up within a heterocyclic ring
Prodrugs activated by external influences
-sleeping agents
Example: Photodynamic therapy - Foscan
HO
OH
HO
H
H
H
NH
N
N
HN
H
OH
Notes:
•Inactive and accumulates in cells
•Activated by light - method of targeting tumour cells
•Foscan is excited and reacts with oxygen to produce toxic singlet oxygen
•Cell destruction is caused by singlet oxygen
Drug Alliances - Synergism
Definition:
Drugs which have a beneficial effect on the activity or
pharmacokinetic properties of another drug
Sentry Drugs
Definition:
A drug that is added to ‘protect’ another drug
Example: Carbidopa
L-DOPA
DOPAMINE
ENZYME
INHIBITION
HO
NHNH2
C
Me
HO
CO2H
CARBIDOPA
Notes
•Carbidopa protects L-dopa
•It inhibits the decarboxylase enzyme in the peripheral blood supply
•It is polar and does not cross the blood brain barrier
•It has no effect on the decarboxylation of L-Dopa in the CNS
•Smaller doses of L-dopa can be administered - less side effects
Other examples: Clavulanic acid and candoxatril
Localizing drugs to a target area
Example:Adrenaline and procaine (local anaesthetic)
•Adrenaline constricts blood vessels at the injection area
•Procaine is localized at the injection area
Increasing absorption
Example: Metoclopramide
O
H
N
N(Et)2
OCH3
Cl
NH2
Notes
•Administered with analgesics in the treatment of migraine
•Increases gastric motility and causes faster absorption of analgesics
•Leads to faster pain relief