1 © Patrick An Introduction to Medicinal Chemistry 3/e Chapter 11 INTRODUCTION TO DRUG DESIGN Part 1: Sections 11.1 – 11.4

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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 1: Sections 11.1 – 11.4Part 1: Sections 11.1 – 11.4

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ContentsContentsPart 1: Sections 11.1 – 11.41. Pharmacokinetics – drug design (2 slides)

1.1. Solubility and membrane permeability1.1.1. Vary alkyl substituents (2 slides)1.1.2. ‘Masking’ or removing polar groups1.1.3. Adding polar groups1.1.4. Vary pKa (2 slides)

1.2. Drug stability1.2.1. Steric Shields1.2.2. ‘Electronic shielding’ of NH2 (2 slides)1.2.3. 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 groups (2 slides)1.2.9. Introducing chemically susceptible groups (2

slides)1.3. Drug targeting

1.3.1. 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 (3 slides)

[29 slides]

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Drug design and developmentDrug design and development

Stages:Stages:

1) Identify target disease1) Identify target disease 2) Identify drug target2) Identify drug target 3) Establish testing procedures3) Establish testing procedures 4) Find a lead compound4) Find a lead compound 5) Structure Activity Relationships (SAR)5) Structure Activity Relationships (SAR) 6) Identify a pharmacophore6) Identify a pharmacophore 7) Drug design - optimising target interactions7) Drug design - optimising target interactions 8) Drug design - optimising pharmacokinetic properties8) Drug design - optimising pharmacokinetic properties 9) Toxicological and safety tests9) Toxicological and safety tests10) Chemical development and production10) Chemical development and production11) Patenting and regulatory affairs11) Patenting and regulatory affairs12) Clinical trials12) Clinical trials

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1. Pharmacokinetics – drug design1. Pharmacokinetics – drug design

AimsAims

• To improve pharmacokinetic properties of lead compoundTo improve pharmacokinetic properties of lead compound

• To optimise chemical and metabolic stability To optimise chemical and metabolic stability (stomach acids / digestive enzymes / metabolic (stomach acids / digestive enzymes / metabolic

enzymes)enzymes)

• To optimise hydrophilic / hydrophobic balance To optimise hydrophilic / hydrophobic balance (solubility in blood / solubility in GIT / solubility (solubility in blood / solubility in GIT / solubility

through through cell membranes / access to CNS / excretion cell membranes / access to CNS / excretion rate)rate)

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• Drugs must be polar - to be soluble in aqueous conditionsDrugs must be polar - to be soluble in aqueous conditions - to interact with molecular - to interact with molecular

targetstargets

• Drugs must be ‘fatty’ - to cross cell membranesDrugs must be ‘fatty’ - to cross cell membranes - to avoid rapid excretion - to avoid rapid excretion

• Drugs must have both hydrophilic and lipophilic Drugs must have both hydrophilic and lipophilic characteristicscharacteristics

• Many drugs are weak bases with pKMany drugs are weak bases with pKaa’s’s 6-8 6-8

Receptor interaction& water solubility

Crossesmembranes

+ H

HN N H

H

- H

1. Pharmacokinetics – drug design1. Pharmacokinetics – drug design

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1.1.1 Vary alkyl substituents1.1.1 Vary alkyl substituents

Rationale:Rationale: • Varying the size of alkyl groups varies the hydrophilic / Varying the size of alkyl groups varies the hydrophilic /

hydrophobic balance of the structurehydrophobic balance of the structure• Larger alkyl groups increase hydrophobicityLarger alkyl groups increase hydrophobicity

DisadvantageDisadvantage:: • May interfere with target binding for steric reasonsMay interfere with target binding for steric reasons

MethodsMethods:: • Often feasible to remove alkyl groups from heteroatoms and Often feasible to remove alkyl groups from heteroatoms and

replace with different alkyl groupsreplace with different alkyl groups• Usually difficult to remove alkyl groups from the carbon Usually difficult to remove alkyl groups from the carbon

skeleton - full synthesis often requiredskeleton - full synthesis often required

1.1 Solubility and membrane permeability1.1 Solubility and membrane permeability

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1.1.1 Vary alkyl substituents1.1.1 Vary alkyl substituents

Methylene ShuffleMethylene 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


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1.1.2 ‘Masking’ or removing polar groups1.1.2 ‘Masking’ or removing polar groups

Rationale:Rationale: • Masking or removing polar groups decreases polarity and Masking or removing polar groups decreases polarity and

increases hydrophobic characterincreases hydrophobic character

Disadvantages:Disadvantages:• Polar group may be involved in target bindingPolar group may be involved in target binding• Unnecessary polar groups are likely to have been removed Unnecessary polar groups are likely to have been removed

already (simplification strategy)already (simplification strategy)• See also prodrugsSee also prodrugs

Methods:Methods:R OH R OMe

CH3I

R NHR

CH3COCl

R

HN

O

CH3

RC

OH

O

H+ / R'OH RC

OR'

O


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1.1.3 Adding polar groups1.1.3 Adding polar groups

Rationale:Rationale:• Adding polar groups increases polarity and decreases Adding polar groups increases polarity and decreases

hydrophobic characterhydrophobic character• Useful for targeting drugs vs. gut infectionsUseful for targeting drugs vs. gut infections• Useful for reducing CNS side effectsUseful for reducing CNS side effects

Disadvantage:Disadvantage: • May introduce unwanted side effectsMay introduce unwanted side effects

Antifungal agent with poor solubility - skin infections only

Cl

Cl

C O

HN

NS

Cl

Tioconazole

Systemic antifungal agent improved blood solubility

F

F

C

OH NN

NNNN

Fluconazole


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1.1.4 Vary pK1.1.4 Vary pKaa

Rationale:Rationale: • Varying pKVarying pKaa alters percentage of drug which is ionised alters percentage of drug which is ionised• Alter pKAlter pKaa to obtain required ratio of ionised to unionised drug to obtain required ratio of ionised to unionised drug

Disadvantage:Disadvantage:• May affect binding interactionsMay affect binding interactions

Method:Method: • Vary alkyl substituents on amine nitrogensVary alkyl substituents on amine nitrogens• Vary aryl substituents to influence aromatic amines or Vary aryl substituents to influence aromatic amines or

aromatic carboxylic acidsaromatic carboxylic acids


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Antithromboticbut too basic

Decreased basicityN locked into heterocycle

1.1.4 Vary pK1.1.4 Vary pKaa

H2N NH

NH

O

N

O

N

N

(I)

amidine

N NH2

NH

O

N

O

N

N

PRO3112


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Terminal amide

StericStericShieldShield

1.2.1 Steric Shields1.2.1 Steric ShieldsRationale:Rationale: • Used to increase chemical and metabolic stabilityUsed to increase chemical and metabolic stability• Introduce bulky group as a shield Introduce bulky group as a shield • Protects a susceptible functional group (e.g. ester) from Protects a susceptible functional group (e.g. ester) from

hydrolysishydrolysis• Hinders attack by nucleophiles or enzymesHinders attack by nucleophiles or enzymes

Blocks hydrolysis of terminal amide

1.2 Drug stability1.2 Drug stability

Antirheumatic agentD1927

HSNH

HN CONHMe

O

O

C

NOO

H3C CH3CH3

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1.2.2 ‘Electronic shielding’ of NH1.2.2 ‘Electronic shielding’ of NH22

Rationale:Rationale: • Used to stabilise labile functional groups (e.g. esters)Used to stabilise labile functional groups (e.g. esters)• Replace labile ester with more stable urethane or amide Replace labile ester with more stable urethane or amide • Nitrogen feeds electrons into carbonyl group and makes it Nitrogen feeds electrons into carbonyl group and makes it

less reactiveless reactive• Increases chemical and metabolic stabilityIncreases chemical and metabolic stability

ISOSTERE

H3CC

O

O O

C

O

H2NR R

ISOSTERE

NH

C

O

CH3H3CC

O

OR R


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1.2.2 ‘Electronic shielding’ of NH1.2.2 ‘Electronic shielding’ of NH22

R NH

C

R'

O

R NH

C

R'

O


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1.2.3 Stereoelectronic Effects1.2.3 Stereoelectronic Effects

Rationale:Rationale: • Steric and electronic effects used in combinationSteric and electronic effects used in combination• Increases chemical and metabolic stabilityIncreases 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 bethanecholSee also: oxacillin and bethanechol

Local anaesthetic(short duration)

PROCAINE

CH2N

O

O CH2CH2NEt2

LIDOCAINE

CH3

CH3

NH

C

CH2NEt2

O


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Rationale:Rationale: • Replace susceptible group with a different group without Replace susceptible group with a different group without

affecting activityaffecting activity• Bio-isostere shows improved pharmacokinetic propertiesBio-isostere shows improved pharmacokinetic properties• Bio-isosteres are not necessarily isosteresBio-isosteres are not necessarily isosteres

Pyrrole ring = bioisostere for amide

Examples:Examples: • Amides and urethanes for esters (see earlier)Amides and urethanes for esters (see earlier)• Du122290 (dopamine antagonist)Du122290 (dopamine antagonist)

1.2.4 Bio-isosteres1.2.4 Bio-isosteres

OMe

EtSO2

NH

NEt

Du122290

OMe

EtSO2

NHO

NEt

Sultopride


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Rationale:Rationale:• Metabolism of drugs usually occur at specific sites. Introduce Metabolism of drugs usually occur at specific sites. Introduce

groups at a susceptible site to block the reactiongroups at a susceptible site to block the reaction• Increases metabolic stability and drug lifetimeIncreases metabolic stability and drug lifetime

Oral contraceptive - limited lifetime

1.2.5 Metabolic blockers1.2.5 Metabolic blockers

MetabolicOxidation

6 MegestrolAcetate

CO

C

H

O

Me

Me

H H

Me OMe

O

MetabolismBlocked

6

Me

Me

O

Me

CO C

H

H H

Me O Me

O


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Rationale:Rationale:• Metabolism of drugs usually occurs at specific groups. Metabolism of drugs usually occurs at specific groups. • Remove susceptible group or replace it with metabolically Remove susceptible group or replace it with metabolically

stable group [stable group [e.g. modification of tolbutamide (antibiotic)]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


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Rationale:Rationale:• Used if the metabolically susceptible group is important for bindingUsed if the metabolically susceptible group is important for binding• Shift its position to make it unrecognisable to metabolic enzyme Shift its position to make it unrecognisable to metabolic enzyme • Must still be recognisable to targetMust still be recognisable 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


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metabolicallysusceptible

Rationale:Rationale:• Used to decrease metabolic stability and drug lifetimeUsed to decrease metabolic stability and drug lifetime• Used for drugs which ‘linger’ too long in the body and cause side Used for drugs which ‘linger’ too long in the body and cause side

effectseffects• Add groups known to be susceptible to Phase I or Phase II Add groups known to be susceptible to Phase I or Phase II

metabolic reactionsmetabolic 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


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labile

labile

Example:Example:Anti-asthmatic agents

• Cromakalim produces cardiovascular side effects if it reaches blood supplyCromakalim produces cardiovascular side effects if it reaches blood supply• Add metabolic instability such that compound rapidly metabolised in Add metabolic instability such that compound rapidly metabolised in

bloodblood• UK143220 - ester quickly hydrolysed by esterases to inactive acidUK143220 - ester quickly hydrolysed by esterases to inactive acid• UK 157147- phenol quickly conjugated and eliminatedUK 157147- phenol quickly conjugated and eliminated

1.2.8 Introducing susceptible metabolic groups1.2.8 Introducing susceptible metabolic groups

O

N

OH

Me

Me

NC

O

34

Cromakalim

O

O

OH

Me

Me

NN

NN

CO2Et

N

O

Me

34

UK143220 O

O

OH

Me

Me

SO2

MeN

N

HO

O

UK157147


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Rationale:Rationale:• Used to decrease drug lifetimeUsed to decrease drug lifetime• Avoids reliance on metabolic enzymes and individual variationsAvoids reliance on metabolic enzymes and individual variations

Example:Example: Atracurium - i.v. neuromuscular blocking agent Atracurium - i.v. neuromuscular blocking agent

• Stable at acid pH, unstable at blood pH (slightly alkaline)Stable at acid pH, unstable at blood pH (slightly alkaline)• Self destructs by Hoffmann elimination and has short lifetimeSelf destructs by Hoffmann elimination and has short lifetime• Allows anaesthetist to control dose levels accuratelyAllows anaesthetist to control dose levels accurately• Quick recovery times after surgeryQuick 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 OC

OMe

O

CH2 CH2

Me

MeO

OMe

OMe

OMe


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HoffmannHoffmannEliminationElimination

1.2.9 Introducing chemically susceptible groups1.2.9 Introducing chemically susceptible groups

NMe

CH2

Ph

CH C

HO

R

ACTIVE

CHH2C C

OPh

RNMe-H

INACTIVE


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Rationale:Rationale:• Drug ‘smuggled’ into cell by carrier proteins for natural building Drug ‘smuggled’ into cell by carrier proteins for natural building

block (e.g. amino acids or nucleic acid bases)block (e.g. amino acids or nucleic acid bases)• Increases selectivity of drugs to target cells and reduces toxicity to Increases selectivity of drugs to target cells and reduces toxicity to

other cellsother cells

Example:Example: Anticancer drugsAnticancer drugs

• Alkylating group is attached to a nucleic acid baseAlkylating group is attached to a nucleic acid base• Cancer cells grow faster than normal cells and have a greater Cancer cells grow faster than normal cells and have a greater

demand for nucleic acid basesdemand for nucleic acid bases• Drug is concentrated in cancer cells - Trojan horse tacticDrug is concentrated in cancer cells - Trojan horse tactic

1.3.1 Linking a biosynthetic building block1.3.1 Linking a biosynthetic building block

1.3 Drug targeting1.3 Drug targeting

Non selective alkylating agentToxic

N

Cl

Cl

H3C

Uracil Mustard

HN

HN

O

O

N

Cl

Cl

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Example:Example:Anticancer agentsAnticancer agents

Rationale:Rationale:• Identify an antigen which is overexpressed on a cancer cellIdentify an antigen which is overexpressed on a cancer cell

• Clone a monoclonal antibody for the antigen Clone a monoclonal antibody for the antigen

• Attach a drug or poison (e.g. ricin) to the monoclonal antibody Attach a drug or poison (e.g. ricin) to the monoclonal antibody

• Antibody carries the drug to the cancer cellAntibody carries the drug to the cancer cell

• Drug is released at the cancer cellDrug is released at the cancer cell

1.3.2 Linking drugs to monoclonal antibodies1.3.2 Linking drugs to monoclonal antibodies


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Rationale:Rationale:• Design the antibacterial agent to be highly polar or ionisedDesign the antibacterial agent to be highly polar or ionised

• 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 ionised sulfonamidesExample - highly ionised sulfonamides

1.3.3 Targeting gut infections1.3.3 Targeting gut infections


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Rationale:Rationale:• Increase polarity of the drugIncrease polarity of the drug

• Drug is less likely to cross the blood brain barrierDrug is less likely to cross the blood brain barrier

1.3.4 Targeting peripheral regions over CNS1.3.4 Targeting peripheral regions over CNS


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Rationale:Rationale:• Toxicity is often due to specific functional groupsToxicity is often due to specific functional groups• Remove or replace functional groups known to be toxic e.g.Remove or replace functional groups known to be toxic e.g.

aromatic nitro groupsaromatic nitro groups aromatic aminesaromatic amines bromoarenesbromoarenes hydrazineshydrazines polyhalogenated groupspolyhalogenated groups hydroxylamineshydroxylamines

• Vary substituentsVary substituents• Vary position of substituentsVary position of substituents

1.4 Reducing drug toxicity1.4 Reducing drug toxicity

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Example - varying substituentsExample - varying substituents

• Fluconazole (Diflucan) - antifungal agentFluconazole (Diflucan) - antifungal agent

Cl

Cl

C

OH NN

NNNN

UK-47265

Substituents variedLess toxic

F

F

C

OH NN

NNNN

Fluconazole


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Example - varying substituent positionExample - varying substituent position

• Dopamine antagonistsDopamine antagonists

Inhibits P450 enzymes

N

HN

ONC

HN

No inhibition of P450 enzymes

N

HN

O

HN

NC


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1 © Patrick An Introduction to Medicinal Chemistry 3/e Chapter 11 INTRODUCTION TO DRUG DESIGN Part 1: Sections 11.1 – 11.4