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 (ADME) 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
•Sometimes beneficial to  size of one alkyl group &  size of another. This is
called methylene shuffle & can modify hydrophobicity of compounds.
8.1 Solubility and membrane permeability
8.1.1 Vary alkyl substituents
Methylene shuffle Extra bulk

CH3 O CH3 O CH3 O

CH3
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

•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)
CH3I
•See also prodrugs R OH R OMe

H
Methods (by masking polar functional R NHR
CH3COCl N CH3
R
group with an alkyl or acyl group)
O
(e.g.: convert alcohol or phenol to ether
or ester; carboxylic acid to ester or amide; R C
OH
H+ / R'OH R OR'
C
primary & secondary amines to amides or O
secondary & tertiary amines) 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

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 Polar hydroxyl group & more polar heterocyclic
solubility - skin infections only (as it is rings added – hence orally active antifungal agent
non-polar & poorly soluble in blood) fluconazole obtained – with improved solubility &
 activity against systemic infection (i.e., in blood
supply)
Disadvantage of adding polar groups
May introduce unwanted side effects
8.1 Solubility and membrane permeability
8.1.4 Vary pKa

Rationale
•Drugs with pKa outside range 6-9 tend to be too strongly ionized, & are poorly
absorbed through cell membranes
•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
8.1 Solubility and membrane permeability
8.1.4 Vary pKa
(No need to study this)

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
8.2 Drug stability
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, amide) 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
(You may read if you wish)
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 H2N O

Isostere

O O

R R
H3C O H3C N
H
Isostere
8.2 Drug stability
(You may read if you wish)
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 (You may read if you wish)
Rationale
•Steric and electronic effects used in combination
•Increases chemical and metabolic stability

O CH3 Lidocaine
H2 N C O
O CH2 CH 2NEt2 N C
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 (No need to study the examples)
Rationale
•Replace susceptible group with a different group without affecting activity
•Bio-isostere shows improved pharmacokinetic properties
•Bio-isosteres are not necessarily isosteres (Bioisostere is a chemical group used to
replace another chemical group in drug, without affecting the important biological
activity)
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 (i.e., specific part of drug).
•Introduce groups at a susceptible site to block the reaction
•Increases drug’s metabolic stability and half life

(See the example only for understanding the concept.)

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). E.g. methyl groups on aromatic rings
often oxidized to carboxylic acids; so remove or replace with group stable to
oxidation. (See the example only for understanding the concept.)

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 (See the example only for understanding the
concept.)
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 Me
OH Me OH
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 – Making Drugs less resistant to metabolism
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
(See the examples in this & in the next slides only for understanding
the concept.)
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
 (No need to study the example)
8.2 Drug stability
8.2.9 Introducing chemically susceptible groups
Rationale
•Used to decrease drug lifetime (drug is called self-destruct drug)
•Avoids reliance on metabolic enzymes, which could vary from patient to patient

Example Atracurium - i.v. neuromuscular blocking agent

MeO O OMe
Me
N O (CH2)5 O N
MeO Me OMe
O

OMe MeO
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

(No need to study this)

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 (to exact location in body where most needed)
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

•Difficulties: identification of suitable antigens

& production of antibodies in significant quantity
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

& so will be prevented from being absorbed into blood supply

•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
& so less likely to have CNS side effects
•Achieving selectivity for CNS over peripheral regions
of body is no so straightforward
8.4 Reducing drug toxicity

Rationale
•Toxicity may be due to toxic metabolites (then drug should be made more
resistant to metabolism) or, often, may be due to specific functional groups
which are particularly prone to producing toxic metabolites.
•In latter case:
• 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
[Link] 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 (You need not study this)
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
[Link] 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
[Link] 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 Levodopa
•Useful in treating Parkinson’s Disease •More polar amino acid
•Too polar to cross cell membranes and BBB •Carried across cell membranes by carrier
proteins for amino acids
•Decarboxylated by decarboxylase enzyme
in cell to dopamine
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
[Link] 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
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 (You need not study this)

Me H
O O
N N

Cl N N-Demethylation Cl N

Valium Nordazepam
8.5.2 Prodrugs to prolong activity
[Link] 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
OH

N N CH2
Me
+ OH
H3N N Me

CO2

Cycloguanil Pamoate
Lipophilic
8.5.2 Prodrugs to prolong activity
[Link] 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)

(You need not study this)

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
(You need not study this)

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
(You need not study this)

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 (You need not study this)
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
H 2O 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

More hydrophobic due to

masked alcohol & long chain
fatty group that forms the ester
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 OH
Cl Esterase H
O O2N
OH
H
Chloramphenicol
O2N

More soluble due to extra

carboxylic acid present
8.5.5 Prodrugs to increase water solubility
Example: Phosphate ester of clindamycin (antibacterial)

(You need not study this)

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 (You need not study this)

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 (7.4)
•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 (intramolecular attack)
•Nitrogen atom in heteracillin is locked up within a heterocyclic ring
•Once administered, hetacillin slowly decomposes to release ampicillin &
acetone.
8.5.8 Prodrugs activated by external influences
-sleeping agents (You need not study this)
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: (You need not study this)
Drugs which have a benefical effect on the activity or
pharmacokinetic properties of another drug
8.6.1 Sentry Drugs
Definition: (You need not study this)
A drug that is added to ‘protect’ another drug
Example: Carbidopa

L-DOPA DOPAMINE
ENZYME

Inhibition
INHIBITION

HO NHNH2
C
Me CO2H

HO CARBIDOPA
CARBIDO PA

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
(You need not study this)
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