Topic 7.2INTRODUCTION TO DRUG

DESIGN

Chapter 11 Patrick

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