1 © 2. Structure Activity Relationships (SAR) Alter, remove or mask a functional groupAlter, remove or mask a functional group Test the analogue for activityTest

1©

2. Structure Activity Relationships (SAR)2. Structure Activity Relationships (SAR)

• Alter, remove or mask a functional groupAlter, remove or mask a functional group• Test the analogue for activityTest the analogue for activity• Conclusions depend on the method of testingConclusions depend on the method of testing

in vitroin vitro - tests for binding interactions with target - tests for binding interactions with targetin vivoin vivo - tests for target binding interactions and/or - tests for target binding interactions and/or

pharmacokineticspharmacokinetics

• If If in vitroin vitro activity drops, it implies group is important for activity drops, it implies group is important for bindingbinding

• If If in vivoin vivo activity unaffected, it implies group is not important activity unaffected, it implies group is not important

AIM - AIM - Identify which functional groups are important for binding Identify which functional groups are important for binding and/or activityand/or activity

METHODMETHOD

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HBD

2.1 SAR on Alcohols2.1 SAR on Alcohols

Possible binding interactionsPossible binding interactions

Possible analoguesPossible analogues

X

Binding site

X= N or O

OH

Drug

O

H

Drug

X

Binding site

H

HBA

R OH R OMeCH3I

CH3COClR

O

O

CH3

CH3SO2Cl

R SO

O

CH3

O

LiAlH4R H

EtherEther

EsterEster

AlkaneAlkane

1©

Possible binding interactionsPossible binding interactions

AnaloguesAnalogues

2.4 SAR on Aldehydes and Ketones2.4 SAR on Aldehydes and Ketones

Dipole-dipoleinteraction

Binding site (X= N or O)

X

H

H-BondingHBA

O

Drug

Binding site

O

Drug

R R'

O NaBH4 or LiAlH4

R R'

HO H

KetonePlanar sp2

carbon centre

2o AlcoholTetrahedral sp 3

carbon centre

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Effect on bindingEffect on binding

Change in stereochemistry (planar to tetrahedral)Change in stereochemistry (planar to tetrahedral)May move oxygen out of range May move oxygen out of range

If still active, further reactions can be carried out on If still active, further reactions can be carried out on alcohol to establish importance of oxygenalcohol to establish importance of oxygen

2.4 SAR on Aldehydes and Ketones2.4 SAR on Aldehydes and Ketones

Binding site (X= N or O)

X

HH

OH

Alcoholanalogue

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• Esters are usually hydrolysed by esterases in the bloodEsters are usually hydrolysed by esterases in the blood• Esters are more likely to be important for Esters are more likely to be important for

pharmacokinetic reasons i.e. acting as prodrugspharmacokinetic reasons i.e. acting as prodrugs

2.5 SAR on Esters2.5 SAR on Esters

Ester masking polar groupsallowing passage throughfatty cell membranes

CO

O

R

OC

R

O

CO

O

R

OC

R

O

COH

O

OH

Prodrug

Prodrug

Fattybarrier

esterase

esterase

Drug

Drug

1©

Possible interactionsPossible interactions

2.10 SAR of Alkyl Groups2.10 SAR of Alkyl Groups

hydrophobic slothydrophobic slot

binding site

Drug

CH3

van der Waalsinteractions

binding site

hydrophobic ‘pocket’hydrophobic ‘pocket’

Drug

CH3CH3

H3C

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AnaloguesAnalogues

• Easiest alkyl groups to vary are substituents on heteroatomsEasiest alkyl groups to vary are substituents on heteroatoms• Vary length and bulk of alkyl group to test space availableVary length and bulk of alkyl group to test space available

2.10 SAR of Alkyl Groups2.10 SAR of Alkyl Groups

N CH3

VOC-ClN H

R'XN R'

HBr R'X

O

CH3O

HO

R'

Hydrolysis R'OH

C

OCH3C

OH

O O H

C

OR'

O

Drug

Drug

Drug

Analogue

Analogue

Analogue

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3. PHARMACOPHORE3. PHARMACOPHORE

• Defines the important groups involved in bindingDefines the important groups involved in binding

• Defines the relative positions of the binding groupsDefines the relative positions of the binding groups

• Need to know Active ConformationNeed to know Active Conformation

• Important to Drug DesignImportant to Drug Design

• Important to Drug DiscoveryImportant to Drug Discovery

1©

O

NMe

HO

HO

MORPHINE

1©

O

NMe

HO

HO

MORPHINE

IMPORTANT GROUPS FOR ANALGESIC ACTIVITYIMPORTANT GROUPS FOR ANALGESIC ACTIVITY

1©

O

NMe

HO

HO

MORPHINE

IMPORTANT GROUPS FOR ANALGESIC ACTIVITYIMPORTANT GROUPS FOR ANALGESIC ACTIVITY

1©

N

HO

ANALGESIC PHARMACOPHORE FOR OPIATESANALGESIC PHARMACOPHORE FOR OPIATES

1©

MORPHINE

O

NMe

HO

HO

NMe

HO

LEVORPHANOL

NMe

HO

METAZOCINE

CH3

H3C

1©

MORPHINE

O

NMe

HO

HO

NMe

HO

LEVORPHANOL

NMe

HO

METAZOCINE

CH3

H3C

1©

O

NMe

HO

HO

1©

1©

OO

NN

ArAr

1©

OO

NN

ArAr

11.3o

150o

18.5o

7.098 A

2.798 A

4.534 A

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4. DRUG DESIGN 4. DRUG DESIGN - OPTIMISING BINDING INTERACTIONS- OPTIMISING BINDING INTERACTIONS

AIMAIM - To optimise binding interactions with target - To optimise binding interactions with target

• To increase activity and reduce dose levelsTo increase activity and reduce dose levels• To increase selectivity and reduce side effectsTo increase selectivity and reduce side effects

STRATEGIESSTRATEGIES • Vary alkyl substituentsVary alkyl substituents• Vary aryl substituentsVary aryl substituents• ExtensionExtension• Chain extensions / contractionsChain extensions / contractions• Ring expansions / contractionsRing expansions / contractions• Ring variationRing variation• IsosteresIsosteres• SimplificationSimplification• RigidificationRigidification

REASONSREASONS

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Salbutamol Salbutamol (Ventolin) (Ventolin) (Anti-asthmatic)(Anti-asthmatic)

AdrenalineAdrenaline

PropranololPropranolol((-Blocker)-Blocker)

4.1 Vary Alkyl Substituents4.1 Vary Alkyl Substituents

OH

O NH

CH3

CH3H

HOCH2

HO

HN

CCH3

OH

CH3

H

CH3

HO

HO

HN

CH3

OHH

1©

-Adrenoceptor-Adrenoceptor

H-Bondingregion

H-Bondingregion

H-Bondingregion

Van der Waalsbonding region

Ionicbondingregion

1©

ADRENALINEADRENALINE


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1©


ADRENALINEADRENALINE

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SALBUTAMOLSALBUTAMOL


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1©



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1©



1©



1©



1©



1©



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Notes on synthetic feasibility of analoguesNotes on synthetic feasibility of analogues

• Feasible to remove alkyl substituents on heteroatomsFeasible to remove alkyl substituents on heteroatomsand replace with other alkyl substituentsand replace with other alkyl substituents

• Difficult to modify alkyl substituents on the carbon skeleton of Difficult to modify alkyl substituents on the carbon skeleton of a lead compound. Full synthesis is usually requireda lead compound. Full synthesis is usually required

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MethodsMethods O

R'

Drug O

H

Drug O

R"

Drug

Ether

N

Me

Drug N

H

Drug N

R"

Drug

R R R

C

OR

Drug C

OH

Drug C

OR"

DrugO O O

O

C

Drug

O

R

OHDrug O

C

Drug

O

R"

NH

C

Drug

O

R

NH2Drug NH

C

Drug

O

R"

C

NR2

Drug C

OH

Drug C

NR2"

Drug

O O O

Amine

Ester

Ester

Amide

Amide

HBra) NaHb) R"I

VOC-Cl R"I

HO-

H+

R"COCl

R"COCl

HNR"2

H+

R"OH

HO-

H+

1©

Example :Example : ACE Inhibitors ACE Inhibitors

4.3 Extension - Extra Functional Groups4.3 Extension - Extra Functional Groups

EXTENSIONEXTENSION

Hydrophobic pocketHydrophobic pocket

Bindingsite

NH

N

O CO2

O

O

CH3

Bindingsite

NH

N

O CO2

O

O

CH3

(I)

Hydrophobic pocketHydrophobic pocket

VacantVacant

1©

ExampleExample

4.5 Ring Expansion / Contraction4.5 Ring Expansion / Contraction

Binding regions

Binding siteBinding site Binding siteBinding site

Vary nto varyring size

NH

(CH2)n

N

N

CO2O

O2C

Ph

N

N

CO2ONH

Ph

O2CNH

N

N

CO2O

O2C

Ph

I

1©

Useful for SARUseful for SAR

• Replacing OCHReplacing OCH22 with CH=CH, SCH with CH=CH, SCH22, CH, CH22CHCH22

eliminates activityeliminates activity• Replacing OCHReplacing OCH22 with NHCH with NHCH22 retains activity retains activity• Implies O involved in binding (HBA)Implies O involved in binding (HBA)

4.7 Isosteres and Bio-isosteres4.7 Isosteres and Bio-isosteres

Propranolol (Propranolol (-blocker)-blocker)

OH

OH

NH

Me

Me

1©

MethodsMethods::• Retain pharmacophore Retain pharmacophore • Remove unnecessary functional groupsRemove unnecessary functional groups

4.8 Simplification4.8 Simplification

OH

NHMe

OMe

HOOC

Ph

Cl

Drug

OH

NHMePh Drug

1©

Methods:Methods:• Remove asymmetric centresRemove asymmetric centres


YN

X

Achiraldrug

YC

X Y

Achiraldrug

YC

X H

Chiraldrug Asymmetric centre

YC

X H

Chiraldrug Asymmetric centre

1©

Methods:Methods:• Simplify in stages to avoid oversimplificationSimplify in stages to avoid oversimplification


• Simplification does not mean ‘pruning groups’ off the lead Simplification does not mean ‘pruning groups’ off the lead compoundcompound

• Compounds usually made by total synthesisCompounds usually made by total synthesis

A

OH

OH

NCH3

B

NCH3

OH

OH

C

OH

OH

NCH3

D

NCH3H

OH

OH

GLIPINE

OH

CH3 OH

H3C

NCH3

PharmacophorePharmacophore

1©

1©

1©

1©

1©

1©Target binding site

Rotatable bonds


Rotatable bonds


Rotatable bonds


Rotatable bonds


Rotatable bonds


Rotatable bonds


Rotatable bonds


Rotatable bonds


Rotatable bonds


Rotatable bonds


Rotatable bonds

1©Different binding site - side effects

Rotatable bonds

1©

Rationale : Rationale : • Endogenous lead compounds often simple and flexible Endogenous lead compounds often simple and flexible (e.g. (e.g.

adrenaline)adrenaline)

• Fit several targets due to different active conformations Fit several targets due to different active conformations (e.g. adrenergic receptor types and subtypes)(e.g. adrenergic receptor types and subtypes)

4.9 Rigidification4.9 Rigidification

• Rigidify molecule to limit conformations - conformational Rigidify molecule to limit conformations - conformational restraintrestraint

• Increases activity (more chance of desired active conformation)Increases activity (more chance of desired active conformation)• Increases selectivity (less chance of undesired active Increases selectivity (less chance of undesired active

conformationsconformations))

Disadvantage:Disadvantage:• Molecule more complex and may be more difficult Molecule more complex and may be more difficult

to synthesiseto synthesise

Flexiblechain

single bondrotation

+ +

Different conformations

1©


BONDROTATION

O H O2C

RECEPTOR 1RECEPTOR 1

O H

O2C

RECEPTOR 2RECEPTOR 2

O

H

H

NH2Me

ONH2Me

H

H

I

O

NH2Me

H

H

II

O

H

H

NH2Me

1©

Methods - Introduce ringsMethods - Introduce ringsBonds within ring systems are locked and cannot rotate freelyBonds within ring systems are locked and cannot rotate freely


Test rigid structures to see which ones have retained active Test rigid structures to see which ones have retained active conformationconformation

HNX

CH3

X NHMe X

NHMe

X

MeN

X

NMe

X

NHMe

Introducingrings

1©

Examples - Examples - Combretastatin (anticancer agent)Combretastatin (anticancer agent)


More active

Less active

RotatableRotatablebondbond

H3CO

H3CO

OCH3

OCH3

OH

Combretastatin A-4

Z-isomerOH

H3CO

H3CO

OCH3

OCH3

OH

Combretastatin

H3CO

H3CO

OCH3

OCH3

OH

E-isomer

1©

Stericclash

Steric Blockers - Steric Blockers - ExamplesExamples


Increase in activityActive conformation retained

Serotonin antagonist

N

HN

N

O

CF3

OMe

N

H

Introducemethyl group

N

HN

N

O

CF3

OMe

N

CH3

H

N

HN

N

O

CF3

OMe

NCH3 H

orthogonalrings

Documents

1 © 2. Structure Activity Relationships (SAR) Alter, remove or mask a functional groupAlter, remove or mask a functional group Test the analogue for activityTest