Post on 30-Dec-2015
transcript
Chapter 14 Pharmacokinetics
Getting a drug to the target in the body
DRUG DESIGN AND DEVELOPMENTDRUG DESIGN AND DEVELOPMENT
StagesStages 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 tests10) Chemical development and production11) Patenting and regulatory affairs12) Clinical trials
PHARMACOKINETICS - DRUG DESIGNPHARMACOKINETICS - 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
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
PHARMACOKINETICS - DRUG DESIGNPHARMACOKINETICS - DRUG DESIGN
Receptor interaction& water solubility
Crossesmembranes
+ H
HN N H
H
- H
Vary alkyl substituentsVary alkyl substituents
Rationale•Varying the size of alkyl groups varies the hydrophilic / hydrophobic balance of the structure•Larger alkyl groups increase hydrophobicity
DisadvantageMay 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 permeabilitySolubility and membrane permeability
Vary alkyl substituents
Methylene shuffleMethylene shuffle
Solubility and membrane permeabilitySolubility and membrane permeability
O
CH3
S OO
N
N
CH3
N
HNN
N
CH3
CH3
O
Viagra
Extra bulkExtra bulk
O
CH3
S OO
N
N
CH3
N
HNN
N
CH3
O
NO
CH3
S OO
N
N
N
HNN
N
H3C
O
N
H3C
UK343664
Methyleneshuffle
•Second-generation anti-impotence agent•Increased selectivity•Excess lipophilicity
Reduced lipophilicityBetter in vivo activity
Extra bulkExtra bulk
O
CH3
S OO
N
N
CH3
N
HNN
N
CH3
O
N
‘‘Masking’ or removing polar groupsMasking’ 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
Methods
Solubility and membrane permeabilitySolubility and membrane permeability
R OH R OMe
CH3I
R NHR
CH3COCl
R
HN
O
CH3
RC
OH
O
H+ / R'OH RC
OR'
O
Systemic antifungal agent improved blood solubility
F
F
C
OH NN
NNNN
Fluconazole
Adding polar groupsAdding polar groupsRationale •Adding polar groups increases polarity and decreases hydrophobic character•Useful for targeting drugs vs. gut infections•Useful for reducing CNS side effects
Disadvantage of adding polar groupsMay introduce unwanted side effects
Solubility and membrane permeabilitySolubility and membrane permeability
Antifungal agent with poor solubility - skin infections only
Cl
Cl
C O
HN
NS
Cl
Tioconazole
Systemic antifungal agent improved blood solubility
F
F
C
OH NN
NNNN
Fluconazole
Vary pKVary pKaa
Rationale •Varying pKa alters percentage of drug which is ionised•Alter pKa to obtain required ratio of ionised to unionised drug
Disadvantage•May affect binding interactions
Method •Vary alkyl substituents on amine nitrogens•Vary aryl substituents to influence aromatic amines or aromatic carboxylic acids
Solubility and membrane permeabilitySolubility and membrane permeability
AntithromboticAntithromboticToo basicToo basic
Decreased basicityDecreased basicityNitrogen locked into heterocyclic ringNitrogen locked into heterocyclic ring
Vary pKVary pKaa
Solubility and membrane permeabilitySolubility and membrane permeability
H2N NH
NH
O
N
O
N
N
(I)
amidine
N NH2
NH
O
N
O
N
N
PRO3112N NH2
NH
O
N
O
N
N
PRO3112
StericStericshieldshield
Steric ShieldsSteric 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
Blocks hydrolysis of Blocks hydrolysis of terminal amideterminal amide
Drug stabilityDrug stability
Antirheumatic agentAntirheumatic agentD1927D1927
HSNH
HN CONHMe
O
O
C
NOO
H3C CH3CH3
Terminal amideTerminal amideAntirheumatic agentAntirheumatic agentD1927D1927
HSNH
HN CONHMe
O
O
C
NOO
H3C CH3CH3
‘ ‘Electronic shielding’ of NHElectronic shielding’ of NH22
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
Drug stabilityDrug stability
ISOSTERE
H3CC
O
O O
C
O
H2NR R
ISOSTERE
NH
C
O
CH3H3CC
O
OR R
‘ ‘Electronic shielding’ of NHElectronic shielding’ of NH22
Drug stabilityDrug stability
R NH
C
R'
O
R NH
C
R'
O
•ortho Methyl groups act as steric shields •Hinder hydrolysis by esterases•Amide more stable than ester (electronic effect)
Stereoelectronic EffectsStereoelectronic Effects
Rationale •Steric and electronic effects used in combination•Increases chemical and metabolic stability
Drug stabilityDrug stability
•Local anaesthetic•Susceptible to esterases•Short duration
CH2N
O
O CH2CH2NEt2ProcaineProcaine
CH3
CH3
NH
C
CH2NEt2
O
LidocaineLidocaineCH3
CH3
NH
C
CH2NEt2
O
LidocaineLidocaine
Rationale •Replace susceptible group with a different group without affecting activity•Bio-isostere shows improved pharmacokinetic properties•Bio-isosteres are not necessarily isosteres
Pyrrole ring = Pyrrole ring = bioisostere for amide bioisostere for amide
Examples •Amides and urethanes for esters (see earlier)•Du122290 (dopamine antagonist)
Bio-isosteresBio-isosteres Drug stabilityDrug stability
OMe
EtSO2
NH
NEt
Du122290
OMe
EtSO2
NHO
NEt
Sultopride
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
•Oral contraceptive•Limited lifetime
Metabolic blockersMetabolic blockers Drug stabilityDrug stability
MetabolicOxidation
6 MegestrolAcetate
CO
C
H
O
Me
Me
H H
Me OMe
O
MetabolismBlocked
6
Me
Me
O
Me
CO C
H
H H
Me O Me
O
Rationale•Remove susceptible group or replace it with a metabolically stable group e.g. modification of tolbutamide (antibiotic)
Susceptible Susceptible groupgroup
Remove / replace susceptible metabolic groupsRemove / replace susceptible metabolic groups Drug stabilityDrug stability
Metabolism
TOLBUTAMIDE
Me S
O
O
NH C
O
NH CH2CH2CH2CH3 NH CH2CH2CH3C
O
NHS
O
O
Cl
Rapidly excreted - short lifetimeRapidly excreted - short lifetime
Metabolism
HOOC S
O
O
NH C
O
NH CH2CH2CH2CH3
Unsusceptible Unsusceptible groupgroup
NH CH2CH2CH3C
O
NHS
O
O
Cl
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
e.g. Salbutamol
Shifting susceptible metabolic groupsShifting susceptible metabolic groups Drug stabilityDrug stability
CatecholO-MethylTransferase
ShiftGroup
Salbutamol
HO C
OH
OH
CH2 NH C
Me
Me
Me
H
C
Me
Me
Me
NHCHCH2
HO
OH
HO
CatecholO-MethylTransferase
HO CHCH2
OH
MeO
NH C
Me
Me
Me
Inactive
Susceptible group
C
Me
Me
Me
NHCHCH2
HO
OH
HO
Unsusceptible group
ShiftGroup
Salbutamol
HO C
OH
OH
CH2 NH C
Me
Me
Me
H
Metabolically Metabolically susceptiblesusceptible
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
Introducing susceptible metabolic groupsIntroducing susceptible metabolic groups Drug stabilityDrug stability
CH2OH
CO2H
SO2Me
N
Cl
NL787257
SO2Me
N
Cl
N CH3L791456
Resistant to metabolismResistant to metabolismExcessively long half lifeExcessively long half life
Examples Anti-asthmatic agents
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
Drug stabilityDrug stability Introducing susceptible metabolic groupsIntroducing susceptible metabolic groups
O
N
OH
Me
Me
NC
O
34
Cromakalim
O
O
OH
Me
Me
NN
NN
CO2Et
N
O
Me
34
UK143220 O
O
OH
Me
Me
SO2
MeN
N
HO
O
UK157147labile
O
O
OH
Me
Me
NN
NN
CO2Et
N
O
Me
34
UK143220
labileO
O
OH
Me
Me
SO2
MeN
N
HO
O
UK157147
Rationale•Used to decrease drug lifetime•Avoids reliance on metabolic enzymes and individual variations
Example Atracurium - i.v. neuromuscular blocking agent
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
Introducing chemically susceptible groupsIntroducing chemically susceptible groups Drug stabilityDrug stability
NCH2 CH2
C
O
O
MeO
OMe
HN
(CH2)5MeO OC
OMe
O
CH2 CH2
Me
MeO
OMe
OMe
OMe
HoffmannElimination
Introducing chemically susceptible groupsIntroducing chemically susceptible groups Drug stabilityDrug stability
NMe
CH2
Ph
CH C
HO
R
ACTIVE
CHH2C C
OPh
RNMe-H
INACTIVE
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
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
Linking a biosynthetic building blockLinking a biosynthetic building block Drug TargetingDrug Targeting
Non selective alkylating agentToxic
N
Cl
Cl
H3C
Uracil Mustard
HN
HN
O
O
N
Cl
Cl
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
Linking drugs to monoclonal antibodiesLinking drugs to monoclonal antibodies Drug TargetingDrug Targeting
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
Targeting gut infectionsTargeting gut infections Drug TargetingDrug Targeting
Rationale•Increase polarity of the drug•Drug is less likely to cross the blood brain barrier
Targeting peripheral regions over CNSTargeting peripheral regions over CNS Drug TargetingDrug Targeting
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 toxicityReducing drug toxicity
Varying substituents•Fluconazole (Diflucan) - antifungal agent
Reducing drug toxicityReducing drug toxicity
Cl
Cl
C
OH NN
NNNN
UK-47265
Substituents variedSubstituents variedLess toxicLess toxic
F
F
C
OH NN
NNNN
Fluconazole
Cl
Cl
C
OH NN
NNNN
UK-47265
Varying substituent position•Dopamine antagonists
Reducing drug toxicityReducing drug toxicity
Inhibits P450 enzymesInhibits P450 enzymes
N
HN
ONC
HN
No inhibition of P450 enzymesNo inhibition of P450 enzymes
N
HN
O
HN
NC
DefinitionInactive 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’
ProdrugsProdrugs
Prodrugs to improve membrane permeabilityProdrugs 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
ExamplesEnalapril for enalaprilate (antihypertensive)
O
NH
O
RO
CO2H
N
CH3
R=Et EnalaprilR=H Enalaprilit
Prodrugs to improve membrane permeabilityProdrugs to improve membrane permeabilityExamplesCandoxatril for Candoxatrilat (protease inhibitor)
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
Candoxatrilat
HN
O
OCO2H
OMe
HO
O
HN
O
OCO2H
OMe
O
O
Candoxatril
5-indanyl group
Prodrugs to improve membrane permeabilityProdrugs to improve membrane permeabilityN-Methylation of amines•Used to reduce polarity of amines•Demethylated in liver
Examples - Hexobarbitone
N NH
Me
O O
O
Me
Dopamine •Useful in treating Parkinson’s Disease•Too polar to cross cell membranes and BBB
Levodopa•More polar amino acid•Carried across cell membranes by carrier proteins for amino acids•Decarboxylated in cell to dopamine
Prodrugs to improve membrane permeabilityProdrugs 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
CH2
CH2
HONH2
HO HO
NH2
C
HO
CH2 CO2H
H
Prodrugs to improve membrane permeabilityProdrugs to improve membrane permeability
COOHH2N
L-Dopa
COOHH2N
Enzyme
Dopamine
H2N
Bloodsupply
Braincells
BLOOD BRAIN BARRIER
Example: Azathioprine for 6-mercaptopurine
Suppresses immune responseShort lifetimeEliminated too quickly
Slow conversion to 6-mercaptopurineLonger lifetime
Prodrugs to prolong activityProdrugs to prolong activity Mask polar groupsMask polar groupsReduces rate of excretion
N
H
SH
NN
N
6-Mercaptopurine6-Mercaptopurine N
NN
N
S N
N
O2N
Me
HAzathioprineAzathioprine
Example: Valium for nordazepam
Prodrugs to prolong activityProdrugs to prolong activity
Valium Nordazepam
N-DemethylationN
NO
Me
Cl Cl
N
HO
N
Example: cycloguanil pamoate (antimalarial)
Add hydrophobic groups•Drug concentrated in fat tissue•Slow removal of hydrophobic group•Slow release into blood supply
Prodrugs to prolong activityProdrugs to prolong activity
LipophilicLipophilic
PamoateCycloguanil
N
N
N
Cl
Me
Me
NH3
H3N
CH2
CO2
OH
OH
CO2
Example: Hydrophobic esters of fluphenazine (antipsychotic)
Prodrugs to prolong activityProdrugs to prolong activity
•Given by intramuscular injection•Concentrated in fatty tissue•Slowly released into the blood supply•Rapidly hydrolysed in the blood supply
S
HN CF3
N
N
O (CH2)8CH3
O
fatty ester
Add hydrophobic groupsAdd hydrophobic groups
Example: Aspirin for salicylic acid
Prodrugs to mask toxicity and side effectsProdrugs to mask toxicity and side effects•Mask groups responsible for toxicity/side effects•Used when groups are important for activity
•Analgesic•Causes stomach ulcers •Due to phenol group
•Phenol masked by ester•Hydrolysed by esterases in bloodstream
OH
CO2H
Salicylic acidSalicylic acid
O
CO2H
O
H3C
AspirinAspirin
Example:Cyclophosphoramide for phosphoramide mustard (anticancer agent)
Prodrugs to mask toxicity and side effectsProdrugs to mask toxicity and side effects
CyclophosphoramideCyclophosphoramide Phosphoramide mustardPhosphoramide mustard
PhosphoramidasePhosphoramidase(liver)(liver)
O
P
NH O
N
Cl
Cl
HO
P
Cl
Cl
N
OH2N
Non toxicOrally active
Alkylating agent
Example: Antiviral drugs
Prodrugs to mask toxicity and side effectsProdrugs to mask toxicity and side effects
N
NN
N NH2HO
OHPenciclovir
Viralthymidinekinase
N
NN
N NH2P O
OH
Cell kinases
N
NN
N NH2O
OH
PPP
Notes•First phosphorylation requires viral thymidine kinase•Only activated in virally infected cells•Non-toxic to uninfected cells
LDZ for diazepam
Prodrugs to mask toxicity and side effectsProdrugs to mask toxicity and side effects
Avoids drowsy side effects of diazepam
Ar O
Cl
N
CH3
O
NH
O
NH2
NH2
LDZ
H a) Aminopeptidasea) Aminopeptidaseb) Cyclisationb) Cyclisation
DiazepamDiazepamCl
N
N
O
CH3
Ar
Prodrugs to mask toxicity and side effectsProdrugs to mask toxicity and side effects
Ar O
Cl
N
CH3
O
NH
O
NH2
NH2
LDZ
H
Enz
-lysine
Ar O
Cl
N
CH3
O
NH2
ClDiazepam
-HN
NAr O
CH3
Cl
N
NO
CH3
H
Ar
Cl
-HN
NAr O
CH3
HO
H
+H
Cl
N
N
ArO
CH3
H2O
H
Mechanism of activation
H
Enz
-lysine
Ar O
Cl
N
CH3
O
NH2
+H
Cl
N
N
ArO
CH3
H2O
H
Prodrugs to lower water solubilityProdrugs 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
O2N
OH
HN
O
O
Cl
ClH
H
O
Esterase
Chloramphenicol
O2N
OH
HN
O
OH
Cl
ClH
H
Prodrugs to increase water solubilityProdrugs 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)
Succinate ester
O2N
OH
HN
O
O
Cl
ClH
H
O
OHO
Esterase
Chloramphenicol
O2N
OH
HN
O
OH
Cl
ClH
H
Prodrugs to increase water solubilityProdrugs to increase water solubilityExample: Phosphate ester of clindamycin (antibacterial)
Less painful on injection
CO N
HC
C
Cl
CH3
O
H
HOOH
OPO32-
SCH3
H
H
H
MeN H
H
HH
CH3CH2CH2
Prodrugs to increase water solubilityProdrugs to increase water solubilityExample: Lysine ester of oestrone
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
H2NO O
NH2
OMe
Prodrug
HH
H
H
H2NO OH
NH2
OMe
HO
Lysine Oestrone
H
H HH
+H2N
O O
NH2
OMe
Prodrug
HH
H
H
Prodrugs used to target drugsProdrugs used to target drugs
Example: Hexamine
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)
NN
N
N
'Locked'Nitrogen
Prodrugs to increase chemical stabilityProdrugs to increase chemical stability
Example: Hetacillin for ampicillin
Notes: •Ampicillin is chemically unstable in solution due to the-NH2 group attacking the-lactam ring•Nitrogen atom in heteracillin is locked up within a heterocyclic ring
HN N
H3C CH3
Ph O
N
S
CH3
CH3
OOH
O
Hetacillin
H2N HN
H3C CH3
Ph O
N
S
CH3
CH3
OOH
O
O
Ampicillin
Prodrugs activated by external influencesProdrugs activated by external influences-sleeping agents-sleeping agents
Example: Photodynamic therapy - Foscan
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
NH N
HNN
OH
HO
HO
OH
HH
HH
Definition:Drugs which have a beneficial effect on the activity or pharmacokinetic properties of another drug
Drug Alliances - SynergismDrug Alliances - Synergism
Definition:A drug that is added to ‘protect’ another drugExample: 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
Sentry DrugsSentry Drugs
Other examples: Other examples: Clavulanic acid and candoxatrilClavulanic acid and candoxatril
L-DOPA DOPAMINEENZYME
INHIBITION
CARBIDOPA
CNHNH2
HO
Me
HO
CO2H
Example:Adrenaline and procaine (local anaesthetic)•Adrenaline constricts blood vessels at the injection area•Procaine is localized at the injection area
Localizing drugs to a target areaLocalizing drugs to a target area
Increasing absorptionIncreasing absorption
Notes•Administered with analgesics in the treatment of migraine•Increases gastric motility and causes faster absorption of analgesics•Leads to faster pain relief
Example: Metoclopramide
Cl
NH2
OCH3
OHN
N(Et)2