Patrick: An Introduction

to Medicinal Chemistry 6e
Chapter 14
DRUG DESIGN
IMPROVING PHARMACOKINETIC
PROPERTIES
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
8. 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

8. PHARMACOKINETICS - DRUG DESIGN
Notes
•Drugs must be sufficiently polar to be soluble in aqueous conditions

•Drugs must be sufficiently polar/fatty to interact with binding sites

•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 pKas 6-8

+H H
N H N H
-H

Crosses Receptor interaction

membranes & water solubility
8.1 Solubility and membrane permeability
8.1.1 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
8.1 Solubility and membrane permeability
8.1.1 Vary alkyl substituents
pyridine ring

Methylene shuffle Extra bulk

CH3 O CH3 CH3 O CH3 O

N N N N N
O HN O HN O HN
N N N
N N N

Methylene H3C
O S O CH3 O S O CH3 shuffle O S O
N N increasing the size of one alkyl group N
+ decreasing the size of another.
Viagra
N N N UK343664
CH3 CH3
H3C

•Second-generation Reduced lipophilicity

anti-impotence agent Better in vivo activity
•Increased selectivity
•Excess lipophilicity
8.1 Solubility and membrane permeability
8.1.2 ‘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 OH R OMe

H
CH3COCl N CH3
R NHR R

R OH
H+ / R'OH R OR'
C
C
O
O
8.1 Solubility and membrane permeability
8.1.3 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
triazole ring
imidazole ring Cl
N N N N N
S OH
N H N N

C O C

Cl F

Cl F
Tioconazole Fluconazole

Antifungal agent with poor

solubility - skin infections only

Disadvantage of adding polar groups

May introduce unwanted side effects
8.1 Solubility and membrane permeability
8.1.4 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
N -alkyl groups have an:
increased electron-donating effect which should increase basicity,
but
increasing the size or number of alkyl groups increases
the steric bulk around the nitrogen atom.
Th is hinders water molecules from solvating the ionized form
of the base and prevents stabilization of the ion. Th is,
in turn, decreases the basicity of the amine
8.1 Solubility and membrane permeability
8.1.4 Vary pKa

N N

O N O N
N N
N N
H H
O O

H2N NH (I) N NH2 PRO3112

amidine

Antithrombotic Decreased basicity

Too basic Nitrogen locked into heterocyclic ring
too basic for eff ective absorption
high pka VS PH 7 so ionized reduced basicity and increased absorption
8.2 Drug stability Making drugs more resistant
to chemical and enzymatic
degradation
8.2.1 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 O
Terminal amide
Antirheumatic agent HS
H
N CH3
D1927 N N
H H
O
C
Steric
H3C CH3
N CH3 shield
O O

Blocks hydrolysis
of terminal amide
8.2 Drug stability
8.2.2 Electronic stabilisation by nitrogen
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

R R
H3C O H2 N O

Isostere

O O

R R
H3C O H3 C N
H
Isostere
8.2 Drug stability
8.2.2 Electronic stabilisation by nitrogen

O O
R N C R N C
H H
R' R'
8.2 Drug stability
8.2.3 Steric and Electronic Effects
Rationale
•Steric and electronic effects used in combination
•Increases chemical and metabolic stability

O CH3 Lidocaine
H2N C O
N C
O CH2CH2NEt2 H
Procaine CH2NEt2
CH3

•Local anaesthetic •ortho Methyl groups act as steric shields

•Susceptible to esterases •Hinder hydrolysis by enzymes
•Short duration •Amide more stable than ester (electronic
effect)

See also: oxacillin and bethanechol

8.2 Drug stability
8.2.4 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)

N NEt
Et
O NH Pyrrole ring =
NH bioisostere for amide
OMe
OMe

EtO2S
Sultopride EtO2S
DU122290
8.2 Drug stability
8.2.5 Metabolic blockers
Rationale:
•Metabolism of drugs usually occurs at specific sites.
•Introduce groups at a susceptible site to block the reaction
•Increases drug’s metabolic stability and half life

Me O
C Me Me O
Me
Me O C Me O
O
Me O
H Me H

H H H
H
O
Megestrol
Megestrol
6 Acetate O 6
acetate Metabolism
Me blocked
Metabolic
oxidation

•Oral contraceptive
•Limited lifetime
8.2 Drug stability
8.2.6 Remove / replace susceptible metabolic groups
Rationale
•Remove susceptible group or replace it with a metabolically stable group e.g.
modification of tolbutamide (antibiotic)

Unsusceptible
Susceptible group
O O
group
Me S NH C NH CH2CH2CH2CH3 Cl S NH C NH CH2CH2CH3
O O O O

TOLBUTAMIDE

Metabolism Metabolism

O
HOOC S NH C NH CH2CH2CH2CH3
O O

Rapidly excreted - short lifetime

8.2 Drug stability
8.2.7 Shifting susceptible metabolic groups
Rationale
•Used if the metabolically susceptible group is important for binding
•Shift its position to make it unrecognisable to metabolic enzymes
•Group must still be recognisable to target
Unsusceptible
e.g. Salbutamol group
OH

Susceptible HO
group Shift H OH Me
OH Me group H
HO CHCH2 NH C Me HO C CH2 N C Me
Me Me
Salbutamol
Catechol
Catechol O-methyl
O-Methyl
transferase
Transferase Catechol
Catechol O-methyl
O-Methyl
transferase
Transferase
MeO
OH Me
HO CHCH2 NH C Me
Me
Inactive
Inactive
8.2 Drug stability
8.2.8 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 N
L787257 N L791456 N CH3

Resistant to metabolism Metabolically CO2H

Excessively long half life susceptible
8.2 Drug stability
8.2.8 Introducing susceptible metabolic groups

Examples Anti-asthmatic agents

O
Me
N O
N N O N N
O N Me
N OH
4
N 3 O
NC OH O O Me
4
3 Me HO S 4
OH
O 3
Me Me Labile
O Me
Me UK143220 O
CO2Et Me
Cromakalim UK157147
Labile

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
8.2 Drug stability
8.2.9 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

b amine loss log chain a hydrolysis ester
MeO O OMe
linkage
Me 4
N O (CH2)5 O N
MeO Me OMe
1 O

OMe MeO 3
2 OMe 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
8.2 Drug stability
8.2.9 Introducing chemically susceptible groups

Hoffmann
Elimination

Me Me
R
N H -H N
C C C R
H2
H O H2C C C
H
Ph Ph O
ACTIVE INACTIVE
8.3 Drug Targeting
8.3.1 Linking a drug to a biosynthetic building block
Rationale:
•Drug ‘smuggled’ into cell by carrier proteins for the 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 H
N
Non selective alkylating agent
Toxic 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
8.3 Drug Targeting
8.3.2 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

8.3 Drug Targeting
8.3.3 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 sulphonamides

8.3 Drug Targeting
8.3.4 Targeting peripheral regions over CNS

Rationale
•Increase polarity of the drug
•Drug is less likely to cross the blood brain barrier
8.4 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

8.4 Reducing drug toxicity

Varying substituents
•Fluconazole (Diflucan) - antifungal agent

N N N N N N N N

N OH N N OH N

C C

Cl F

Cl F

UK-47265 Fluconazole

Toxic side effects due Substituents varied

to Cl substituents Less toxic
8.4 Reducing drug toxicity

Varying substituent position

•Dopamine antagonists

HN
H HN
N H
N
NC O
N O
N

NC

Inhibits P450 enzymes No inhibition of P450 enzymes

8.5 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’
8.5.1 Prodrugs to improve membrane permeability
8.5.1.1 Esters
•Used to mask polar carboxylic acids, alcohols or phenols
•Hydrolysed in blood by esterases
•Used when a carboxylic acid, alcohol or phenol is required for target binding
•Leaving group (alcohol or carboxylic acid) should ideally be non toxic

Examples
Enalapril for enalaprilate (antihypertensive)

CH3
RO N
N
H
O O CO2H

R=Et Enalapril
R=H Enalaprilit
8.5.1 Prodrugs to improve membrane permeability
Examples
Candoxatril for candoxatrilat (protease inhibitor)

OMe OMe

O O

H H
HO N O N

O O O O
CO2H CO2H
Candoxatril
Candoxatrilat 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
8.5.1 Prodrugs to improve membrane permeability
8.5.1.2 N-Methylation of amines
•Used to reduce polarity of amines
•Demethylated in liver

Examples - Hexobarbitone

Me
N NH

O O
Me
8.5.1 Prodrugs to improve membrane permeability
8.5.1.2 Trojan Horse Strategy
•Prodrug designed to mimic biosynthetic building block
•Transported across cell membranes by carrier proteins

Example - Levodopa for dopamine

HO HO CO2H
H
NH2 NH2
HO HO

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
 Drug

Cell
Membrane Transport
Cell RECEPTOR
Membrane Protein

Cell
 Cell
Membrane Transport
Cell RECEPTOR
Membrane Protein

Cell
 Cell
Membrane Transport
Cell RECEPTOR
Membrane Protein

Cell
 Cell
Membrane Transport
Cell RECEPTOR
Membrane Protein

Cell
 Cell
Membrane Transport
Cell RECEPTOR
Membrane Protein

Cell
 Cell
Membrane Transport
Cell RECEPTOR
Membrane Protein

Cell
 Cell
Membrane Transport
Cell RECEPTOR
Membrane Protein

Cell
 Cell
Membrane Transport
Cell RECEPTOR
Membrane Protein

Cell
 Cell
Membrane Transport
Cell RECEPTOR
Membrane Protein

Cell
 Cell
Membrane Transport
Cell RECEPTOR
Membrane Protein

Cell
 Cell
Membrane Transport
Cell RECEPTOR
Membrane Protein

Cell
 Cell
Membrane Transport
Cell RECEPTOR
Membrane Protein

Cell
 Cell
Membrane Transport
Cell RECEPTOR
Membrane Protein

Cell
 Cell
Membrane Transport
Cell RECEPTOR
Membrane Protein

Cell
 Cell
Membrane Transport
Cell RECEPTOR
Membrane Protein

Cell
 Cell
Membrane Transport
Cell RECEPTOR
Membrane Protein

Cell
8.5.1 Prodrugs to improve membrane permeability

Blood Brain
supply cells

H2N COOH
H2N COOH

L-Dopa Enzyme

L-Dopa H2N

Dopamine
BLOOD BRAIN
BARRIER
8.5.2 Prodrugs to prolong activity
8.5.2.1 Mask polar groups
Reduces rate of excretion

Example: Azathioprine for 6-mercaptopurine

O2N
N
SH

N S N
N
pyrimidine Me
N
N
N N
H
N N
6-Mercaptopurine
H
Azathioprine

Suppresses immune response Slow conversion to 6-mercaptopurine

Short lifetime Longer lifetime
Eliminated too quickly
8.5.2 Prodrugs to prolong activity
Example: Valium for nordazepam

Me H
O O
N N

Cl N N-Demethylation Cl N

Valium Nordazepam

-Demethylation is a common metabolic reaction in

the liver, so polar amines can be N -methylated to reduce
polarity and improve membrane permeability
8.5.2 Prodrugs to prolong activity
8.5.2.2 Add hydrophobic groups
•Drug concentrated in fat tissue
•Slow removal of hydrophobic group
•Slow release into blood supply
Th e antimalarial
agent cycloguanil pamoate ( Fig. 14.26 ) is one such
agent. Th e active drug is bound ionically to an anion containing
a large lipophilic group and is only released into
the blood supply following slow dissociation of the ion
complex.

Example: Cycloguanil pamoate (antimalarial)

CO2

+ Cl
NH3
OH

N N CH2
Me
+ OH
H3N N Me

CO2

Cycloguanil Pamoate
Lipophilic
8.5.2 Prodrugs to prolong activity
8.5.2.2 Add hydrophobic groups

Example: Hydrophobic esters of fluphenazine (antipsychotic)

fatty ester
N

N O (CH2)8CH3

H
N CF3

•Given by intramuscular injection

•Concentrated in fatty tissue
•Slowly released into the blood supply
•Rapidly hydrolysed in the blood supply
8.5.3 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 Aspirin

•Analgesic •Phenol masked by ester

•Causes stomach ulcers •Hydrolysed by esterases
•Due to phenol group in bloodstream
8.5.3 Prodrugs to mask toxicity and side effects
Example: Cyclophosphoramide for phosphoramide mustard (anticancer agent)

NH O Cl H2N O Cl
Phosphoramidase
P P
(liver)
N HO N
O

Cl Cl
Cyclophosphoramide Phosphoramide mustard

Non toxic Alkylating agent

Orally active
 8.5.3 Prodrugs to mask toxicity and side effects
Example: Antiviral drugs

O O O

N N N
NH NH NH
HO PO P P PO
N N NH2 N N N NH2
N NH2

Viral Cell kinases

thymidine
OH kinase OH OH
Penciclovir

Notes
•First phosphorylation requires viral thymidine kinase
•Only activated in virally infected cells
•Non-toxic to uninfected cells
8.5.3 Prodrugs to mask toxicity and side effects
Example: LDZ for diazepam

Ar O
CH3 O
H N
N NH2 a) Aminopeptidase Ar
O
N b) Cyclisation
H
N
O
Cl CH3

LDZ Cl
LDZ
Diazepam
NH2

Avoids drowsy side effects of diazepam

8.5.3 Prodrugs to mask toxicity and side effects
Mechanism of activation
Ar O H
CH3 O H
H N
N NH2 Ar O Ar
N CH3 NH2 O
H Enz -H HO
O N N
Cl -lysine CH3
LDZ O
Cl Cl
NH2

H H
N N N
H2O Ar Ar
O O O
+H Ar -H
N N N
CH3 CH3 CH3

Cl Cl Cl
Diazepam
8.5.4 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 Cl
H H
N
O O Cl Cl
H H
N O
Cl OH
Esterase H
O
OH O2N
H
O2N
Chloramphenicol
8.5.5 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 Cl
H H
N
O O Cl Cl
H H O
N
Cl OH
Esterase H
O
OH O2N
H
Chloramphenicol
O2N
8.5.5 Prodrugs to increase water solubility
Example: Phosphate ester of clindamycin (antibacterial)

CH3CH2CH2 Me H
N
Cl H
H
C C CH3
H O N C
H
HO O H
OH H
H SCH3
H OPO32-

Less painful on injection

8.5.5 Prodrugs to increase water solubility
Example: Lysine ester of estrone

O O
Me Me

H H H H H H
NH2 NH2
H + H
H2N H2N
O O O OH HO
Prodrug Lysine Estrone

Notes:
•Lysine ester of estrone is better absorbed orally than estrone
•Increased water solubility prevents it dissolving in fat globules in the gut
•Better interaction with the gut wall
•Hydrolysis in blood releases estrone and a non toxic amino acid
8.5.6 Prodrugs used to target drugs

Example: Hexamine

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)
8.5.7 Prodrugs to increase chemical stability

Example: Hetacillin for ampicillin

Ph O Ph O
Ampicillin
HN N CH3 H2N HN
S S CH3

H3C CH3 CH3 CH3

'Locked' N O N
Nitrogen O O
OH OH
Hetacillin O H3C CH3 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
8.5.8 Prodrugs activated by external influences
-sleeping agents
Example: Photodynamic therapy - Foscan
HO

OH
NH N

N HN
HO H
H
H 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
8.6 Drug Alliances - Synergism
Definition:
Drugs which have a benefical effect on the activity or
pharmacokinetic properties of another drug
8.6.1 Sentry Drugs
Definition:
A drug that is added to ‘protect’ another drug
Example: Carbidopa

L-DOPA DOPAMINE
ENZYME

Inhibition
INHIBITION

HO NHNH2
C
Me CO2H

HO CARBIDOPA
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

8.6.2 Localising drugs to a target area
Example: Adrenaline and procaine (local anaesthetic)
•Adrenaline constricts blood vessels at the injection area
•Procaine is localised at the injection area

8.6.3 Increasing absorption

H
Example: Metoclopramide O 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
 Patrick: An Introduction
to Medicinal Chemistry 6e
Chapter 14

PEPTIDOMIMETICS

© Oxford University Press, 2013

1. Peptides as Drugs
Notes
•Peptides and proteins act as neurotransmitters, hormones, and
enzyme substrates
•Important lead compounds in drug design
•Resulting drugs are inevitably peptide-like

Disadvantages of peptide-like drugs

•Pharmacokinetic properties are often unsatisfactory
•Susceptible to digestive and metabolic enzymes
•Poor absorption from the digestive tract
•Difficulty in crossing cell membranes
•Poor aqueous solubility
•Lack of oral activity
•Poor bio-availability
© Oxford University Press, 2013
2. Peptidomimetics
Aims
•Modify peptide-like drugs to make them less peptide-like

•Increase resistance to digestive and metabolic enzymes

•Increase water solubility

•Increase oral absorption and bio-availability

© Oxford University Press, 2013

3. Strategies - replacing a susceptible peptide bond
Some peptide bonds are prone to hydrolysis by enzymes

O R O R
Enzyme
N OH + H N
R H R H
Active peptide Inactive metabolites

Strategy
•Replace with a stable functional group
•The functional group should mimic the important features of the target
peptide bond and act as a bio-isostere
•Peptide bonds are planar
•Peptide bonds may participate in H-bonding with the target binding site

HBA
O R
N
R H
HBD
© Oxford University Press, 2013
3. Strategies - replacing a susceptible peptide bond
Examples of possible bio-isosteres
O R H R
•Alkene matches the planar nature of the
N peptide bond, but
R H R H •Unable to participate in H-bonding
Peptide Alkene

O R O R •Ketone retains carbonyl oxygen (HBA) but

•Lacks HBD
N •Non-planar in nature
R H R H •Increased flexibility
Peptide Ketone

O R R •Amine retains NH (HBD), but

N •Lacks HBA
N
•Non-planar in nature
R H R H •Increased flexibility
Peptide Amine

O R S R •Thioamide matches the planar nature of

N N the peptide bond
•Contains NH (HBD), but
R H R H •Lacks carbonyl group (HBA)
Peptide Thioamide
© Oxford University Press, 2013
4. Strategies - disguising a peptide bond
N-Methylation
O R O R
N N
R H R CH3
Peptide N-Methylation

Notes
•Planar peptide bond retained
•Carbonyl oxygen retained as HBA
•N-Methyl group may act as a steric shield to block digestive and metabolic
enzymes
•Lacks N-H (HBD)
•Detrimental if forms important interaction to target binding site
•Beneficial if forms important interaction to digestive or metabolic enzymes

© Oxford University Press, 2013

5. Strategies - altering stereochemistry
Inverting an asymmetric centre

R1 O R1 O
H H
N L N L
N L N D
H H
O R2 O R2

Notes
•Replace an L-amino acid with a D-amino acid
•Unnatural amino acid not recognised by digestive or metabolic enzymes
•Side chain or residue unable to bind to binding pocket
•Stabilises a neighbouring susceptible peptide bond
•But may not be recognised by target binding site

© Oxford University Press, 2013

6. Strategies - introducing an unnatural residue
O

O H
H
N
H
N
H

L-Proline Decahydroisoquinoline ring

Notes
•Replace a natural amino-acid side chain with an unnatural side chain
•Unnatural side chain not recognised by digestive or metabolic enzymes
•Can be designed to form important binding interactions with target binding
site
•Increases activity and selectivity

© Oxford University Press, 2013

7. Strategies - extended side chains
Subsite 3 Subsite 3

Subsite 1 R3 Subsite 1
Extended
residue
R1 O
O
H H
N OH N
N N N OH
H H H
O R2 O O R2

Subsite 2 Subsite 2
Notes
•Extend a side chain such that it binds to two binding subsites
•Allows truncation of the main scaffold chain and reduced molecular weight
•Can lead to better oral bioavailability
•Can be designed to form important binding interactions with target binding
site
•Increases activity and selectivity

© Oxford University Press, 2013

8. Strategies - introduce polar groups
O H
H

N
Exposed residue
remains solv ated

O
H
N
N
H
O R2

Binding site

Notes
•Introduce an unnatural side chain with polar group
•Polar group is solvated and increases aqueous solubility
•Polar group should protrude from binding site
•Remains solvated - no desolvation energy penalty
•Can lead to better oral bioavailability

© Oxford University Press, 2013

 9. Strategies - rigidification
•Flexiblity is related to poor oral bioavailability
•Introduce rings to ‘lock’ bonds

macrocycle
Macrocycle

NH2 HN
Phe
Asn
Me Me Me Me
O O O O O O
H H H H
N N P N N P
N O CO2R N O CO2R
H OH H OH
O O O O
Me Me Me2HC Me Me Me2HC

Acyclic pentapeptide ( Ki 42 nM) Rigidified pentapeptide (Ki 0.1 nM)

© Oxford University Press, 2013