patrick an introduction to medicinal chemistry 3/e chapter 11 introduction to drug design

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Patrick Patrick An Introduction to Medicinal An Introduction to Medicinal

ChemistryChemistry 3/e 3/e

Chapter 11 Chapter 11

INTRODUCTION TO DRUG INTRODUCTION TO DRUG DESIGNDESIGN

Part 2: Sections 11.5 – 11.6Part 2: Sections 11.5 – 11.6

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ContentsContentsPart 2: Sections 11.5 – 11.6

1.5. Prodrugs1.5.1. Prodrugs to improve membrane permeability

1.5.1.1. Esters (2 slides)1.5.1.2. N-Methylation of amines1.5.1.3. Trojan Horse Strategy (20 slides)

1.5.2. Prodrugs to prolong activity1.5.2.1. Mask polar groups1.5.2.2. Add hydrophobic groups (2 slides)

1.5.3. Prodrugs to mask toxicity and side effects (5 slides)1.5.4. Prodrugs to lower water solubility1.5.5. Prodrugs to increase water solubility (3 slides)1.5.6. Prodrugs used to target drugs1.5.7. Prodrugs to increase chemical stability1.5.8. Prodrugs activated by external influences -sleeping

agents1.6. Drug alliances - synergism

1.6.1. Sentry Drugs1.6.2. Localising drugs to a target area1.6.3. Increasing absorption

[45 slides]

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Definition:Definition:Inactive compounds which are converted to active Inactive compounds which are converted to active compounds in the body.compounds in the body.

Uses:Uses: • Improving membrane permeabilityImproving membrane permeability• Prolonging activityProlonging activity• Masking toxicity and side effectsMasking toxicity and side effects• Varying water solubilityVarying water solubility• Drug targetingDrug targeting• Improving chemical stabilityImproving chemical stability• ‘‘Sleeping agents’Sleeping agents’

1.5 Prodrugs1.5 Prodrugs

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1.5.1 Prodrugs to improve membrane permeability1.5.1 Prodrugs to improve membrane permeability

1.5.1.1 Esters1.5.1.1 Esters• Used to mask polar and ionisable carboxylic acidsUsed to mask polar and ionisable carboxylic acids• Hydrolysed in blood by esterasesHydrolysed in blood by esterases• Used when a carboxylic acid is required for target bindingUsed when a carboxylic acid is required for target binding• Leaving group (alcohol) should ideally be non toxicLeaving group (alcohol) should ideally be non toxic

Example:Example:Enalapril for enalaprilate (antihypertensive)Enalapril for enalaprilate (antihypertensive)

O

NH

O

RO

CO2H

N

CH3

R=Et EnalaprilR=H Enalaprilit

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Example:Example:Candoxatril for Candoxatrilat (protease inhibitor)Candoxatril for Candoxatrilat (protease inhibitor)

• Varying the ester varies the rate of hydrolysisVarying the ester varies the rate of hydrolysis• Electron withdrawing groups increase rate of hydrolysisElectron withdrawing groups increase rate of hydrolysis

(e.g. 5-indanyl)(e.g. 5-indanyl)• Leaving group (5-indanol) is non toxicLeaving group (5-indanol) is non toxic

Candoxatrilat

HN

O

OCO2H

OMe

HO

O

HN

O

OCO2H

OMe

O

O

Candoxatril

5-indanyl group

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1.5.1.2 1.5.1.2 NN-Methylation of amines-Methylation of amines

• Used to reduce polarity of aminesUsed to reduce polarity of amines• Demethylated in liverDemethylated in liver

Example:Example:HexobarbitoneHexobarbitone

N NH

Me

O O

O

Me

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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 amino acids

• Decarboxylated in cell to dopamine


1.5.1.3 Trojan Horse Strategy1.5.1.3 Trojan Horse Strategy

• Prodrug designed to mimic biosynthetic building blockProdrug designed to mimic biosynthetic building block• Transported across cell membranes by carrier proteinsTransported across cell membranes by carrier proteins

Example: Example: Levodopa for dopamine

CH2

CH2

HONH2

HO HO

NH2

C

HO

CH2 CO2H

H

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CellMembrane

Cell

RECEPTOR

Cell Membrane

CarrierProtein

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CellMembrane

Cell

RECEPTOR

Cell Membrane

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Cell

Cell Membrane

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COOHH2N

L-Dopa

COOHH2N

Enzyme

Dopamine

H2N

Bloodsupply

Braincells

BLOOD BRAIN BARRIER

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Example:Example: Azathioprine for 6-mercaptopurineAzathioprine for 6-mercaptopurine

6-Mercaptopurine(suppresses immune response)• Short lifetime - eliminated too quickly

Azathioprine• Slow conversion to 6-mercaptopurine• Longer lifetime

1.5.2 Prodrugs to prolong activity1.5.2 Prodrugs to prolong activity

1.5.2.1 Mask polar groups1.5.2.1 Mask polar groups

• Reduces rate of excretionReduces rate of excretion

N

H

SH

NN

N

N

NN

N

S N

N

O2N

Me

H

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Example:Example: Valium for nordazepamValium for nordazepam


Valium Nordazepam

N-DemethylationN

NO

Me

Cl Cl

N

HO

N

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Example:Example:Cycloguanil pamoate (antimalarial)Cycloguanil pamoate (antimalarial)

1.5.2.2 Add hydrophobic groups1.5.2.2 Add hydrophobic groups

• Drug concentrated in fat tissueDrug concentrated in fat tissue• Slow removal of hydrophobic groupSlow removal of hydrophobic group• Slow release into blood supplySlow release into blood supply


LipophilicLipophilic

PamoateCycloguanil

N

N

N

Cl

Me

Me

NH3

H3N

CH2

CO2

OH

OH

CO2

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Example:Example: Hydrophobic esters of fluphenazine (antipsychotic)Hydrophobic esters of fluphenazine (antipsychotic)


1.5.2.2 Add hydrophobic groups1.5.2.2 Add hydrophobic groups

• Given by intramuscular injectionGiven by intramuscular injection• Concentrated in fatty tissueConcentrated in fatty tissue• Slowly released into the blood supplySlowly released into the blood supply• Rapidly hydrolysed in the blood supplyRapidly hydrolysed in the blood supply

S

HN CF3

N

N

O (CH2)8CH3

O

fatty ester

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Example:Example:Aspirin for salicylic acidAspirin for salicylic acid

1.5.3 Prodrugs to mask toxicity and side effects1.5.3 Prodrugs to mask toxicity and side effects• Mask groups responsible for toxicity/side effectsMask groups responsible for toxicity/side effects• Used when groups are important for activityUsed when groups are important for activity

Salicylic acid• Analgesic, but causes stomachulcers due to phenol group

Aspirin• Phenol masked by ester• Hydrolysed in body

OH

CO2H O

CO2H

O

H3C

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Example:Example: Cyclophosphoramide for phosphoramide mustard Cyclophosphoramide for phosphoramide mustard

(anticancer agent)(anticancer agent)

1.5.3 Prodrugs to mask toxicity and side effects1.5.3 Prodrugs to mask toxicity and side effects

CyclophosphoramideCyclophosphoramide• Non toxicNon toxic• Orally activeOrally active

Phosphoramide mustardPhosphoramide mustard• Alkylating agentAlkylating agent

Phosphoramidase(liver)

O

P

NH O

N

Cl

Cl

HO

P

Cl

Cl

N

OH2N

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Example:Example:Antiviral drugsAntiviral drugs


N

NN

N NH2HO

OHPenciclovir

Viralthymidinekinase

N

NN

N NH2P O

OH

Cell kinases

N

NN

N NH2O

OH

PPP

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Example:Example:LDZ for diazepamLDZ for diazepam


LDZ• Avoids drowsy side effects of diazepam

Ar O

Cl

N

CH3

O

NH

O

NH2

NH2

LDZ

H

Diazepam

a) Aminopeptidaseb) Cyclisation

Cl

N

N

O

CH3

Ar

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H

Ar O

Cl

N

CH3

O

NH

O

NH2

NH2

LDZ

H

Enz

-lysine

Ar O

Cl

N

CH3

O

NH2

ClDiazepam

-HN

NAr O

CH3

Cl

N

NO

CH3

H

Ar

Cl

-HN

NAr O

CH3

HO

H

+H

Cl

N

N

ArO

CH3

H2O

H

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1.5.4 Prodrugs to lower water solubility1.5.4 Prodrugs to lower water solubility• Used to reduce solubility of foul tasting orally active drugs Used to reduce solubility of foul tasting orally active drugs • Less soluble on tongueLess soluble on tongue• Less revolting tasteLess revolting taste

Example:Example:Palmitate ester of chloramphenicol (antibiotic)Palmitate ester of chloramphenicol (antibiotic)

Palmitate ester

O2N

OH

HN

O

O

Cl

ClH

H

OEsterase

Chloramphenicol

O2N

OH

HN

O

OH

Cl

ClH

H

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1.5.5 Prodrugs to increase water solubility1.5.5 Prodrugs to increase water solubility• Often used for i.v. drugs Often used for i.v. drugs • Allows higher concentration and smaller dose volumeAllows higher concentration and smaller dose volume• May decrease pain at site of injectionMay decrease pain at site of injection

Example:Example:Succinate ester of chloramphenicol (antibiotic)Succinate ester of chloramphenicol (antibiotic)

Succinate ester

O2N

OH

HN

O

O

Cl

ClH

H

O

OHO

Esterase

Chloramphenicol

O2N

OH

HN

O

OH

Cl

ClH

H

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1.5.5 Prodrugs to increase water solubility1.5.5 Prodrugs to increase water solubility

Example:Example:Phosphate ester of clindamycin (antibacterial)Phosphate ester of clindamycin (antibacterial)

• Less painful on injection

CO N

HC

C

Cl

CH3

O

H

HOOH

OPO32-

SCH3

H

H

H

MeN H

H

HH

CH3CH2CH2

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1.5.5 Prodrugs to increase water solubility1.5.5 Prodrugs to increase water solubility

Example:Example:Lysine ester of oestroneLysine ester of oestrone

• Lysine ester of oestrone is better absorbed orally than oestroneLysine ester of oestrone is better absorbed orally than oestrone

• Increased water solubility prevents formation of fat globules in gutIncreased water solubility prevents formation of fat globules in gut

• Better interaction with the gut wallBetter interaction with the gut wall

• Hydrolysis in blood releases oestrone and a non toxic amino acid Hydrolysis in blood releases oestrone and a non toxic amino acid

H2NO O

NH2

OMe

Prodrug

HH

H

H

H2NO OH

NH2

OMe

HO

Lysine Oestrone

H

H HH

+

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1.5.6 Prodrugs used to target drugs1.5.6 Prodrugs used to target drugs

Example:Example:HexamineHexamine

• Stable and inactive at pH>5Stable and inactive at pH>5• Stable at blood pHStable at blood pH• Used for urinary infections where pH<5 Used for urinary infections where pH<5 • Degrades at pH<5 to form formaldehyde (antibacterial agent)Degrades at pH<5 to form formaldehyde (antibacterial agent)

NN

N

N

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1.5.7 Prodrugs to increase chemical stability1.5.7 Prodrugs to increase chemical stability

Example:Example:Hetacillin for ampicillinHetacillin for ampicillin

• Ampicillin is chemically unstable in solution due to theAmpicillin is chemically unstable in solution due to the--NHNH22 group attacking the group attacking the-lactase ring-lactase ring

• ‘‘N’ in heteracillin is locked up within a heterocyclic ringN’ in heteracillin is locked up within a heterocyclic ring

'Locked'Nitrogen

HN N

H3C CH3

Ph O

N

S

CH3

CH3

OOH

O

Hetacillin

H2N HN

H3C CH3

Ph O

N

S

CH3

CH3

OOH

O

O

Ampicillin

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1.5.8 Prodrugs activated by external influences1.5.8 Prodrugs activated by external influences-sleeping agents-sleeping agents

Example: Example: Photodynamic therapy - FoscanPhotodynamic therapy - Foscan

• Inactive and accumulates in cellsInactive and accumulates in cells• Activated by light - method of targeting tumour cellsActivated by light - method of targeting tumour cells• Foscan is excited and reacts with oxygen to produce toxic singlet Foscan is excited and reacts with oxygen to produce toxic singlet

oxygenoxygen• Cell destruction is caused by singlet oxygenCell destruction is caused by singlet oxygen

NH N

HNN

OH

HO

HO

OH

HH

HH

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Definition:Definition:Drugs which have a benefical effect on the activity or Drugs which have a benefical effect on the activity or pharmacokinetic properties of another drugpharmacokinetic properties of another drug

1.6 Drug alliances - synergism1.6 Drug alliances - synergism

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Definition:Definition:A drug that is added to ‘protect’ another drugA drug that is added to ‘protect’ another drug

Example:Example: CarbidopaCarbidopa

• Carbidopa protects L-dopaCarbidopa protects L-dopa• It inhibits the decarboxylase enzyme in the peripheral blood supplyIt inhibits the decarboxylase enzyme in the peripheral blood supply• It is polar and does not cross the blood brain barrierIt is polar and does not cross the blood brain barrier• It has no effect on the decarboxylation of L-Dopa in the CNSIt has no effect on the decarboxylation of L-Dopa in the CNS• Smaller doses of L-dopa can be administered - less side effectsSmaller doses of L-dopa can be administered - less side effects

1.6.1 Sentry Drugs1.6.1 Sentry Drugs

Other examples:Other examples: Clavulanic acid and candoxatrilClavulanic acid and candoxatril

L-DOPA DOPAMINEENZYME

INHIBITION

CARBIDOPA

CNHNH2

HO

Me

HO

CO2H

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Example: Example: Adrenaline and procaine (local anaesthetic)Adrenaline and procaine (local anaesthetic)

• Adrenaline constricts blood vessels at the injection areaAdrenaline constricts blood vessels at the injection area• Procaine is localised at the injection areaProcaine is localised at the injection area

1.6.2 Localising drugs to a target area1.6.2 Localising drugs to a target area

1.6.3 Increasing absorption1.6.3 Increasing absorption

• Administered with analgesics in the treatment of migraineAdministered with analgesics in the treatment of migraine• Increases gastric motility and causes faster absorption of Increases gastric motility and causes faster absorption of

analgesicsanalgesics• Leads to faster pain reliefLeads to faster pain relief

Example:Example: MetoclopramideMetoclopramide

Cl

NH2

OCH3

OHN

N(Et)2

patrick an introduction to medicinal chemistry 3/e chapter 11 introduction to drug design

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