Topic 7.

2
INTRODUCTION TO DRUG
DESIGN

Chapter 11 Patrick
Contents
Part 1: Sections 11.1 – 11.4
1. Pharmacokinetics – drug design
1.1. Solubility and membrane permeability
1.1.1. Vary alkyl substituents
1.1.2. ‘Masking’ or removing polar groups
1.1.3. Adding polar groups
1.1.4. Vary pKa
1.2. Drug stability
1.2.1. Steric Shields
1.2.2. ‘Electronic shielding’ of NH2
1.2.3. Stereoelectronic Effects
1.2.4. Bio-isosteres
1.2.5. Metabolic blockers
1.2.6. Remove / replace susceptible metabolic groups
1.2.7. Shifting susceptible metabolic groups
1.2.8. Introducing susceptible metabolic groups
1.2.9. Introducing chemically susceptible groups
1.3. Drug targeting
1.3.1. Linking a biosynthetic building block
1.3.2. Linking drugs to monoclonal antibodies
1.3.3. Targeting gut infections
1.3.4. Targeting peripheral regions over CNS
1.4. Reducing drug toxicity
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 - optimising target interactions
8) Drug design - optimising pharmacokinetic properties
9) Toxicological and safety tests
10) Chemical development and production
11) Patenting and regulatory affairs
12) Clinical trials
1. Pharmacokinetics – drug design

Aims

• 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)
1. Pharmacokinetics – drug design
• 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

+H H

N H N H
-H

Crosses Receptor interaction

membranes & water solubility
1.1 Solubility and membrane permeability
1.1.1 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 permeability
1.1.1 Vary alkyl substituents
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 N

Viagra
N N N UK343664
CH3 CH3
H3C
1.1 Solubility and membrane permeability
1.1.2 ‘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 CH I 3
R OH R OMe
Methods:
CH3COCl H
N CH3
R NHR R

R OH
C H+ / R'OH R OR'
C
O
O
1.1 Solubility and membrane permeability
1.1.3 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
Cl
N N N N
N
S N OH N
N H
C
C O
F
Cl

F
Cl
Fluconazole
Tioconazole
Antifungal agent with poor Systemic antifungal agent
solubility - skin infections only improved blood solubility

Disadvantage:
• May introduce unwanted side effects
1.1 Solubility and membrane permeability
1.1.4 Vary pKa
Rationale:
• Varying pKa alters percentage of drug which is ionized
• 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
1.1 Solubility and membrane permeability
1.1.4 Vary pKa

N N

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

H2N NH (I) PRO3112

N NH2
amidine

Antithrombotic Decreased basicity

but too basic N locked into heterocycle
1.2 Drug stability
1.2.1 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
Antirheumatic agent H Terminal amide
HS N CONHMe
D1927 N
H
O
C Steric
H3C CH3 Shield
N CH3
O O

Blocks hydrolysis of terminal amide

1.2 Drug stability
1.2.2 ‘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 C R
R
H3C O H2N O

ISOSTERE
O O

C R C R
H3C O CH3 NH

ISOSTERE
1.2 Drug stability
1.2.2 ‘Electronic shielding’ of NH2

O O

R N C R N C
H H
R' R'

See carbamoylcholine
1.2 Drug stability
1.2.3 Stereoelectronic Effects
Rationale:
• Steric and electronic effects used in combination
• Increases chemical and metabolic stability

O CH3

H2N C O

O CH2CH2NEt2 N C
H
CH2NEt2
PROCAINE CH3
LIDOCAINE
Local anaesthetic
(short duration) ortho Methyl groups act as steric shields &
hinder hydrolysis by esterases
Amide more stable than ester
(electronic effect)

See also: oxacillin and bethanechol

1.2 Drug stability
1.2.4 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)

NEt NEt
Pyrrole ring =
O NH NH bioisostere for amide

OMe OMe

EtSO2 EtSO2
Sultopride Du122290
1.2 Drug stability
1.2.5 Metabolic blockers
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

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

H H
H H
6 Megestrol 6
O
Acetate O
Metabolism
Me Blocked

Metabolic
Oxidation
Oral contraceptive
- limited lifetime
1.2 Drug stability
1.2.6 Remove / replace susceptible metabolic groups
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)]

Unsusceptible
Susceptible O group 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

1.2 Drug stability
1.2.7 Shifting susceptible metabolic groups
Rationale:
• Used if the metabolically susceptible group is important for binding
• Shift its position to make it unrecognisable to metabolic enzyme
• Must still be recognizable to target
Example: Unsusceptible
group
Salbutamol OH

Susceptible HO
Shift
group OH Me Group H OH Me
HO CHCH2 NH C Me HO C CH2 NH C Me
Me Me
Salbutamol
Catechol
O-Methyl
Transferase Catechol
O-Methyl
Transferase
MeO
OH Me
HO CHCH2 NH C Me
Me

Inactive
1.2 Drug stability
1.2.8 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
Example:
Anti-arthritic agents SO2Me
SO2Me
Cl
CH2OH
Cl
N
N
L791456 N CH3
L787257 N CO2H
metabolically
susceptible
1.2 Drug stability
1.2.9 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
MeO OMe
O O
Me H
N C C N
MeO CH2 CH2 O (CH2)5 O CH2 CH2 OMe

OMe MeO
OMe OMe

• 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
1.3 Drug targeting
1.3.1 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
Cl Cl
Example: O
Anticancer drugs H3C N N
HN

Cl Cl
O H
N
Non selective alkylating agent
Toxic Uracil Mustard
• 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 Drug targeting
1.3.2 Linking drugs to monoclonal antibodies

Example:
Anticancer agents

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 Drug targeting
1.3.3 Targeting gut infections

Rationale:
• Design the antibacterial agent to be highly polar or ionized
• Agent will be too polar to cross the gut wall
• Agent will be concentrated at the site of infection
• Example - highly ionized sulfonamides
1.3 Drug targeting
1.3.4 Targeting peripheral regions over CNS

Rationale:
• Increase polarity of the drug
• Drug is less likely to cross the blood brain barrier
1.4 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
1.4 Reducing drug toxicity
Example - 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

Substituents varied
Less toxic
Contents
Part 2: Sections 11.5 – 11.6

1.5. Prodrugs
1.5.1. Prodrugs to improve membrane permeability
1.5.1.1. Esters
1.5.1.2. N-Methylation of amines
1.5.1.3. Trojan Horse Strategy
1.5.2. Prodrugs to prolong activity
1.5.2.1. Mask polar groups
1.5.2.2. Add hydrophobic groups
1.5 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
1.5.1 Prodrugs to improve membrane permeability
1.5.1.1 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 toxic
Example:
Enalapril for enalaprilate (antihypertensive)

CH3
RO N
N
H
O O CO2H

R=Et Enalapril
R=H Enalaprilit
1.5.1 Prodrugs to improve membrane permeability
Example:
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

• 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
1.5.1 Prodrugs to improve membrane permeability
1.5.1.2 N-Methylation of amines

• Used to reduce polarity of amines

• Demethylated in liver

Example: O
Hexobarbitone Me
N NH

O O
Me
1.5.1 Prodrugs to improve membrane permeability
1.5.1.3 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 CO2H
CH2 C
H
NH2 NH2
HO HO

Dopamine Levodopa
• Useful in treating Parkinson’s • More polar but is an amino acid
Disease • Carried across cell membranes
• Too polar to cross cell membranes by carrier proteins for amino
and BBB acids
• Decarboxylated in cell to
dopamine
1.5.1 Prodrugs to improve membrane permeability

Blood Brain
supply cells

H2N COOH
H2N COOH

L-Dopa Enzyme
H2N

Dopamine
BLOOD BRAIN
BARRIER
1.5.2 Prodrugs to prolong activity
1.5.2.1 Mask polar groups
• Reduces rate of excretion

Example:
Azathioprine for 6-mercaptopurine
O2N
N
SH

N S N
N
N Me
N
N N
H
N N
H

6-Mercaptopurine Azathioprine
(suppresses immune response) • Slow conversion to 6-mercaptopurine
• Short lifetime - eliminated too quickly • Longer lifetime
1.5.2 Prodrugs to prolong activity
Example:
Valium for nordazepam

Me H
O O
N N

Cl N N-Demethylation Cl N

Valium Nordazepam
1.5.2 Prodrugs to prolong activity
1.5.2.2 Add hydrophobic groups
• Drug (and counterion) concentrated in fat tissue
• Slow removal of hydrophobic group
• Slow release into blood supply
Example:
Cycloguanil pamoate (antimalarial)
CO2

Cl
NH3
OH

N N CH2
Me
OH
H3N N Me

CO2

Cycloguanil Pamoate
Lipophilic
1.5.2 Prodrugs to prolong activity
1.5.2.2 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