topic 7.2 introduction to drug design · introduction to drug design chapter 11 patrick. contents...
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ContentsContentsPart 1: Sections 11.1 – 11.41. Pharmacokinetics – drug design
1.1. Solubility and membrane permeability1.1.1. Vary alkyl substituents1.1.2. ‘Masking’ or removing polar groups1.1.3. Adding polar groups1.1.4. Vary pKa
1.2. Drug stability1.2.1. Steric Shields1.2.2. ‘Electronic shielding’ of NH21.2.3. Stereoelectronic Effects1.2.4. Bio-isosteres1.2.5. Metabolic blockers1.2.6. Remove / replace susceptible metabolic groups1.2.7. Shifting susceptible metabolic groups1.2.8. Introducing susceptible metabolic groups1.2.9. Introducing chemically susceptible groups
1.3. Drug targeting1.3.1. Linking a biosynthetic building block1.3.2. Linking drugs to monoclonal antibodies1.3.3. Targeting gut infections1.3.4. Targeting peripheral regions over CNS
1.4. Reducing drug toxicity
Drug design and developmentDrug design and development
Stages: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 - optimising target interactions 8) Drug design - optimising pharmacokinetic properties 9) Toxicological and safety tests10) Chemical development and production11) Patenting and regulatory affairs12) Clinical trials
1. Pharmacokinetics 1. Pharmacokinetics –– drug design drug design
AimsAims
• To improve pharmacokinetic properties of lead compound
• To optimise chemical and metabolic stability (stomach acids / digestive enzymes / metabolic enzymes)
• To optimise hydrophilic / hydrophobic balance (solubility in blood / solubility in GIT / solubility through cell membranes / access to CNS / excretion rate)
• Drugs must be polar - to be soluble in aqueous conditions - to interact with molecular targets
• Drugs must be ‘fatty’ - to cross cell membranes - to avoid rapid excretion
• Drugs must have both hydrophilic and lipophilic characteristics
• Many drugs are weak bases with pKa’s 6-8
Receptor interaction& water solubility
Crossesmembranes
+ H
HN N H
H
- H
1. Pharmacokinetics 1. Pharmacokinetics –– drug design drug design
1.1.1 Vary alkyl substituents1.1.1 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
1.1 Solubility and membrane permeability1.1 Solubility and membrane permeability
1.1.1 Vary alkyl 1.1.1 Vary alkyl substituentssubstituents
Methylene Methylene Shuffle!Shuffle!
O
CH3
S OO
N
N
CH3
N
HNN
N
CH3
CH3
O
Viagra
Extra 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
1.1 Solubility and membrane permeability1.1 Solubility and membrane permeability
1.1.2 1.1.2 ‘‘MaskingMasking’’ or removing polar groups or removing polar groupsRationale: • 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:R OH R OMe
CH3I
R NHR
CH3COCl
R
HN
O
CH3
R
C
OH
O
H+ / R'OH R
C
OR'
O
1.1 Solubility and membrane permeability1.1 Solubility and membrane permeability
1.1.3 Adding polar groups1.1.3 Adding polar groupsRationale:Rationale:• Adding polar groups increases polarity and decreases hydrophobic
character• Useful for targeting drugs vs. gut infections• Useful for reducing CNS side effects
Disadvantage:Disadvantage: • May introduce unwanted side effects
Antifungal agent with poor solubility - skin infections only
Cl
Cl
C O
HN
N
S
Cl
Tioconazole
Systemic antifungal agent improved blood solubility
F
F
C
OH NN
NNNN
Fluconazole
1.1 Solubility and membrane permeability1.1 Solubility and membrane permeability
1.1.4 Vary 1.1.4 Vary pKpKaa
Rationale: • Varying pKa alters percentage of drug which is ionized• 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
1.1 Solubility and membrane permeability1.1 Solubility and membrane permeability
Antithromboticbut too basic
Decreased basicityN locked into heterocycle
1.1.4 Vary 1.1.4 Vary pKpKaa
H2N NH
NH
O
N
O
N
N
(I)
amidine
N NH2
NH
O
N
O
N
N
PRO3112
1.1 Solubility and membrane permeability1.1 Solubility and membrane permeability
Terminal amide
StericStericShieldShield
1.2.1 Steric Shields1.2.1 Steric ShieldsRationale:• 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 terminal amide
1.2 Drug stability1.2 Drug stability
Antirheumatic agentD1927 HS
NH
HN CONHMe
O
O
C
NOO
H3C CH3
CH3
1.2.2 1.2.2 ‘‘Electronic shieldingElectronic shielding’’ of NH 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
ISOSTERE
H3C
C
O
O O
C
O
H2NR R
ISOSTERE
NH
C
O
CH3H3C
C
O
O
R R
1.2 Drug stability1.2 Drug stability
1.2.2 1.2.2 ‘‘Electronic shieldingElectronic shielding’’ of NH of NH22
R NH
C
R'
O
R NH
C
R'
O
1.2 Drug stability1.2 Drug stability
See carbamoylcholine
1.2.3 1.2.3 Stereoelectronic Stereoelectronic EffectsEffects
Rationale: • Steric and electronic effects used in combination• Increases chemical and metabolic stability
ortho Methyl groups act as steric shields &hinder hydrolysis by esterasesAmide more stable than ester(electronic effect)
See also: oxacillin and See also: oxacillin and bethanecholbethanechol
Local anaesthetic(short duration)
PROCAINE
CH2N
O
O CH2CH2NEt2
LIDOCAINE
CH3
CH3
NH
C
CH2NEt2
O
1.2 Drug stability1.2 Drug stability
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 = bioisostere for amide
Examples: • Amides and urethanes for esters (see earlier)• Du122290 (dopamine antagonist)
1.2.4 1.2.4 Bio-isosteresBio-isosteres
OMe
EtSO2
NH
NEt
Du122290
OMe
EtSO2
NHO
NEt
Sultopride
1.2 Drug stability1.2 Drug stability
Rationale:• Metabolism of drugs usually occur at specific sites. Introduce
groups at a susceptible site to block the reaction• Increases metabolic stability and drug lifetime
Oral contraceptive - limited lifetime
1.2.5 Metabolic blockers1.2.5 Metabolic blockers
Metabolic
Oxidation
6 MegestrolAcetate
CO
C
H
O
Me
Me
H H
Me O
Me
O
Metabolism
Blocked
6
Me
Me
O
Me
C
O C
H
H H
Me OMe
O
1.2 Drug stability1.2 Drug stability
Rationale:• Metabolism of drugs usually occurs at specific groups.• Remove susceptible group or replace it with metabolically stable
group [e.g. modification of tolbutamide (antibiotic)]
Susceptible group
Unsusceptible group
1.2.6 Remove / replace susceptible metabolic groups1.2.6 Remove / replace susceptible metabolic groups
Metabolism
TOLBUTAMIDE
Me S
O
O
NH C
O
NH CH2CH2CH2CH3 NH CH2CH2CH3C
O
NHS
O
O
Cl
Rapidly excreted - short lifetime
Metabolism
HOOC S
O
O
NH C
O
NH CH2CH2CH2CH3
1.2 Drug stability1.2 Drug stability
Rationale:Rationale:• Used if the metabolically susceptible group is important for binding• Shift its position to make it unrecognisable to metabolic enzyme• Must still be recognizable to targetExample:Example:
SalbutamolSalbutamolSusceptible group
Unsusceptible group
1.2.7 Shifting susceptible metabolic groups1.2.7 Shifting susceptible metabolic groups
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
1.2 Drug stability1.2 Drug stability
metabolicallysusceptible
Rationale: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
Example:Example:Anti-arthritic agents
1.2.8 Introducing susceptible metabolic groups1.2.8 Introducing susceptible metabolic groups
CH2OH
CO2H
SO2Me
N
Cl
NL787257
SO2Me
N
Cl
N CH3L791456
1.2 Drug stability1.2 Drug stability
Rationale:• Used to decrease drug lifetime• Avoids reliance on metabolic enzymes and individual variations
Example:Example: Atracurium Atracurium - i.v. neuromuscular blocking agent- 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
1.2.9 Introducing chemically susceptible groups1.2.9 Introducing chemically susceptible groups
NCH2 CH2
C
O
O
MeO
OMe
HN
(CH2)5MeO O
C
OMe
O
CH2 CH2
Me
MeO
OMe
OMe
OMe
1.2 Drug stability1.2 Drug stability
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
• 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
1.3.1 Linking a biosynthetic building block1.3.1 Linking a biosynthetic building block1.3 Drug targeting1.3 Drug targeting
Non selective alkylating agentToxic
N
Cl
Cl
H3C
Uracil Mustard
H
N
HN
O
O
N
Cl
Cl
Example:Example:Anticancer agents
Rationale:Rationale:• 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
1.3.2 Linking drugs to monoclonal antibodies1.3.2 Linking drugs to monoclonal antibodies1.3 Drug targeting1.3 Drug targeting
Rationale:Rationale:•• Design the antibacterial agent to be highly polar or ionizedDesign the antibacterial agent to be highly polar or ionized•• Agent will be too polar to cross the gut wallAgent will be too polar to cross the gut wall•• Agent will be concentrated at the site of infectionAgent will be concentrated at the site of infection•• Example - highly ionized Example - highly ionized sulfonamidessulfonamides
1.3.3 Targeting gut infections1.3.3 Targeting gut infections1.3 Drug targeting1.3 Drug targeting
Rationale:Rationale:• Increase polarity of the drug• Drug is less likely to cross the blood brain barrier
1.3.4 Targeting peripheral regions over CNS1.3.4 Targeting peripheral regions over CNS
1.3 Drug targeting1.3 Drug targeting
Rationale: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
1.4 Reducing drug toxicity1.4 Reducing drug toxicity
Example - varying Example - varying substituentssubstituents
•• Fluconazole Fluconazole ((DiflucanDiflucan) - antifungal agent) - antifungal agent
Cl
Cl
C
OH NN
NNN
N
UK-47265
Substituents variedLess toxic
F
F
C
OH NN
NNN
N
Fluconazole
1.4 Reducing drug toxicity1.4 Reducing drug toxicity
ContentsContentsPart 2: Sections 11.5 – 11.6
1.5. Prodrugs1.5.1. Prodrugs to improve membrane permeability
1.5.1.1. Esters1.5.1.2. N-Methylation of amines1.5.1.3. Trojan Horse Strategy
1.5.2. Prodrugs to prolong activity1.5.2.1. Mask polar groups1.5.2.2. Add hydrophobic groups
Definition:Definition:Inactive compounds which are converted to active compounds inthe body.
Uses: • Improving membrane permeability• Prolonging activity• Masking toxicity and side effects• Varying water solubility• Drug targeting• Improving chemical stability
1.5 1.5 ProdrugsProdrugs
1.5.1 1.5.1 Prodrugs Prodrugs to improve membrane permeabilityto improve membrane permeability1.5.1.1 Esters1.5.1.1 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 toxicExample:Example:
EnalaprilEnalapril for for enalaprilateenalaprilate (antihypertensive) (antihypertensive)
O
NH
O
RO
CO2H
N
CH3
R=Et EnalaprilR=H Enalaprilit
1.5.1 1.5.1 Prodrugs Prodrugs to improve membrane permeabilityto improve membrane permeabilityExample:Example:
CandoxatrilCandoxatril for for CandoxatrilatCandoxatrilat (protease inhibitor) (protease inhibitor)
• 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
1.5.1 1.5.1 Prodrugs Prodrugs to improve membrane permeabilityto improve membrane permeability1.5.1.2 1.5.1.2 NN-Methylation -Methylation of aminesof amines
• Used to reduce polarity of amines• Demethylated in liver
Example:Example:HexobarbitoneHexobarbitone
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 but is an amino acid• Carried across cell membranes
by carrier proteins for aminoacids
• Decarboxylated in cell todopamine
1.5.1 Prodrugs to improve membrane permeability1.5.1 Prodrugs to improve membrane permeability1.5.1.3 Trojan Horse Strategy1.5.1.3 Trojan Horse Strategy• Prodrug designed to mimic biosynthetic building block• Transported across cell membranes by carrier proteins
Example: Example: Levodopa for dopamineCH2
CH2
HONH2
HOHO
NH2
C
HO
CH2 CO2H
H
1.5.1 1.5.1 Prodrugs Prodrugs to improve membrane permeabilityto improve membrane permeability
COOHH2N
L-Dopa
COOHH2N
Enzyme
Dopamine
H2N
Bloodsupply
Braincells
BLOOD BRAIN BARRIER
Example:Example: Azathioprine Azathioprine for 6-mercaptopurinefor 6-mercaptopurine
6-Mercaptopurine(suppresses immune response)• Short lifetime - eliminated too quickly
Azathioprine• Slow conversion to 6-mercaptopurine• Longer lifetime
1.5.2 1.5.2 Prodrugs Prodrugs to prolong activityto prolong activity1.5.2.1 Mask polar groups1.5.2.1 Mask polar groups• Reduces rate of excretion
N
H
SH
NN
N
N
NN
N
S N
N
O2N
Me
H
Example:Example: Valium Valium for for nordazepamnordazepam
1.5.2 Prodrugs to prolong activity1.5.2 Prodrugs to prolong activity
Valium Nordazepam
N-DemethylationN
N
O
Me
Cl Cl
N
H
O
N
Example:Example:Cycloguanil pamoate Cycloguanil pamoate ((antimalarialantimalarial))
1.5.2.2 Add hydrophobic groups1.5.2.2 Add hydrophobic groups• Drug (and counterion) concentrated in fat tissue• Slow removal of hydrophobic group• Slow release into blood supply
1.5.2 1.5.2 Prodrugs Prodrugs to prolong activityto prolong activity
LipophilicLipophilicPamoateCycloguanil
N
N
N
Cl
Me
Me
NH3
H3N
CH2
CO2
OH
OH
CO2
Example:Example: Hydrophobic esters of Hydrophobic esters of fluphenazine fluphenazine (antipsychotic)(antipsychotic)
1.5.2 Prodrugs to prolong activity1.5.2 Prodrugs to prolong activity1.5.2.2 Add hydrophobic groups1.5.2.2 Add hydrophobic groups
• Given by intramuscular injection• Concentrated in fatty tissue• Slowly released into the blood supply• Rapidly hydrolysed in the blood supply
S
H
N CF3
N
N
O (CH2)8CH3
O
fatty ester