Patrick An Introduction to Medicinal Chemistry 3/e Chapter 10 DRUG DESIGN:

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Patrick Patrick An Introduction to Medicinal An Introduction to Medicinal

ChemistryChemistry 3/e 3/e

Chapter 10Chapter 10

DRUG DESIGN: DRUG DESIGN: OPTIMIZING TARGET OPTIMIZING TARGET

INTERACTIONSINTERACTIONS

Part 1: Section 10.1 (SAR)Part 1: Section 10.1 (SAR)

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ContentsContents

Part 1: Section 10.1 (SAR)

1. Introduction to drug design & development2. Structure Activity Relationships (SAR) (2 slides)

2.1. SAR on Alcohols (2 slides)2.2. SAR on 1o, 2o & 3o Amines (RNH2, RNHR, R3N) (4 slides)2.3. SAR on Quaternary Ammonium Salts (R4N+) 2.4. SAR on Aldehydes and Ketones (2 slides)2.5. SAR on Esters (2 slides) 2.6. SAR on Amides (3 slides)2.7. SAR on Carboxylic Acids (3 slides)2.8. SAR on Aromatic Rings and Alkenes (2 slides)2.9. Miscellaneous Functional Groups in Drugs 2.10. SAR of Alkyl Groups (2 slides)

[26 slides]

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1. Introduction to drug design & development1. Introduction to drug design & development

StagesStages

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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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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NOTES ON ANALOGUESNOTES ON ANALOGUES

• Modifications may disrupt binding by electronic / steric effectsModifications may disrupt binding by electronic / steric effects

• Easiest analogues to make are those made from lead compoundEasiest analogues to make are those made from lead compound

• Possible modifications may depend on other groups presentPossible modifications may depend on other groups present

• Some analogues may have to be made by a full synthesisSome analogues may have to be made by a full synthesis(e.g. replacing an aromatic ring with a cyclohexane ring)(e.g. replacing an aromatic ring with a cyclohexane ring)

• Allows identification of important groups involved in bindingAllows identification of important groups involved in binding

• Allows identification of the pharmacophoreAllows identification of the pharmacophore

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

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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

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Possible effect of analogues on bindingPossible effect of analogues on binding(e.g. ether)(e.g. ether)

2.1 SAR on Alcohols2.1 SAR on Alcohols

X

Binding site

X= N or OX

Binding site

H

No interaction as HBD No interaction as HBA

steric shield

OCH3

Ether analogue

OCH3

Ether analogue

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Possible binding interactions if amine is ionisedPossible binding interactions if amine is ionised

2.2 SAR on 12.2 SAR on 1oo, 2, 2oo & 3 & 3oo Amines Amines (RNH(RNH22, RNHR, R, RNHR, R33N)N)

IonicIonic

H-BondingH-Bonding

HBD

X

Binding site

X= N or O

CO2-

Binding site

NH2R

Drug

+

NH

Drug

R2

+RR33NNHH acts as a acts as a

strong HBDstrong HBD

+

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Possible binding interactions for free basePossible binding interactions for free base


H-BondingH-Bonding

HBD

X

Binding site

X= N or OX

Binding site

H

HBA

NH

Drug

RN

R

Drug

H

Note: Note: 33oo Amines are only able to act as HBA’s - no hydrogen available to act as HBD Amines are only able to act as HBA’s - no hydrogen available to act as HBD

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Analogues ofAnalogues of11oo & 2 & 2oo amines amines

Effect on bindingEffect on binding


CO2-

Binding site

No interaction

N CH3

O

R

Amide analogue

• 11oo and 2 and 2oo amines are converted to 2 amines are converted to 2oo and 3 and 3oo amides respectively amides respectively• Amides cannot ionise and so ionic bonding is not possibleAmides cannot ionise and so ionic bonding is not possible• An amide N is a poor HBA and so this eliminates HBA interactionsAn amide N is a poor HBA and so this eliminates HBA interactions• Steric effect of acyl group is likely to hinder NSteric effect of acyl group is likely to hinder NHH acting as a HBD (2 acting as a HBD (2oo amide) amide)

R NH2

CH3COCl

R

HN

O

CH3

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Analogues of 3Analogues of 3oo amines containing a methyl substituent amines containing a methyl substituent


R NHRCH3COCl

R

RN

O

CH3R NHR

CH3

VOC-Cl

O CH3

O

Demethylation

2o amine

3o amide

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AnaloguesAnalogues Full synthesis of 1Full synthesis of 1oo-3-3oo amines and amides amines and amides

2.3 SAR on Quaternary Ammonium Salts 2.3 SAR on Quaternary Ammonium Salts (R(R44NN++))

CO2-

Binding site

Ionicbonding

NR3

Drug

+

NR3

Drug

+

Induceddipole interactions

Binding site

+-

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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


X

HH

OH

Alcoholanalogue

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Possible binding interactionsPossible binding interactions H-bonding as HBA by either oxygenH-bonding as HBA by either oxygen

AnaloguesAnalogues

• Hydrolysis splits molecule and may lead to a loss of activity due to loss of Hydrolysis splits molecule and may lead to a loss of activity due to loss of other functional groups - only suitable for simple esters. other functional groups - only suitable for simple esters.

• Hydrolysis leads to a dramatic increase in polarity which may influence Hydrolysis leads to a dramatic increase in polarity which may influence ability of analogue to reach target if ability of analogue to reach target if in vivoin vivo tests are used tests are used

• Reduction to alcohol removes carbonyl group and can establish Reduction to alcohol removes carbonyl group and can establish importance of the carbonyl oxygen, but reaction can be difficult to do if importance of the carbonyl oxygen, but reaction can be difficult to do if

other labile functional groups are presentother labile functional groups are present

2.5 SAR on Esters2.5 SAR on Esters

RC

O

O

CH3

LiAlH4

NaOH RC

OH

O

CH3HO

RCH2

OH

+

Carboxylic acid Alcohol

1o Alcohol

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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

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• The nitrogen of an amide cannot act as a HBA - lone pair The nitrogen of an amide cannot act as a HBA - lone pair interacts with neighbouring carbonyl groupinteracts with neighbouring carbonyl group

• Tertiary amides unable to act as HBD’sTertiary amides unable to act as HBD’s

2.6 SAR on Amides2.6 SAR on Amides


X

H


X

HBAHBDN

Drug

H

O

R

N

Drug

H

O

R

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AnaloguesAnalogues

• Hydrolysis splits molecule and may lead to loss of activity due to loss of Hydrolysis splits molecule and may lead to loss of activity due to loss of other functional groups - only suitable for simple amides. other functional groups - only suitable for simple amides.

• Hydrolysis leads to dramatic increase in polarity which may affect ability Hydrolysis leads to dramatic increase in polarity which may affect ability of analogue to reach target if of analogue to reach target if in vivoin vivo tests are done tests are done

• Reduction to amine removes carbonyl group and can establish importance Reduction to amine removes carbonyl group and can establish importance of the carbonyl oxygen, but reaction may be difficult to do if other labile of the carbonyl oxygen, but reaction may be difficult to do if other labile groups are present groups are present

2.6 SAR on Amides2.6 SAR on Amides R

C

HN

O

R'

LiAlH4

NaOH RC

OH

O

R'H2N

RCH2

NH2

+

NaH / MeIR

C

CH3N

O

R'

Carboxylic acid Amine

1o Amine

3o Amide

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2.6 SAR on Amides2.6 SAR on Amides

• NN-Methylation prevents HBD interaction and may introduce a steric -Methylation prevents HBD interaction and may introduce a steric effect that prevents an HBA interactioneffect that prevents an HBA interaction

No binding as HBD

X

N

CH3

O

R

Analogue

binding site

Binding of O as HBA hindered

X

H

N

CH3

R

O

steric shield

Analogue

AnaloguesAnalogues

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Possible binding interactions as free acidPossible binding interactions as free acid

2.7 SAR on Carboxylic Acids2.7 SAR on Carboxylic Acids


X

HHBA


X

H

HBAC

OH

Drug

O

C

OH

Drug

O


X

HC

O

Drug

O

HBD

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Possible binding interactions as carboxylate ionPossible binding interactions as carboxylate ion



X

HHBA


NHR2+

Ionic bonding

OC

O

Drug

-

OC

O

Drug

-

• Charged oxygen atoms are strong HBA’sCharged oxygen atoms are strong HBA’s• Group could interact both as an ion and as a HBA at the same Group could interact both as an ion and as a HBA at the same

timetime

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Possible effectsPossible effects• Reduction removes carbonyl oxygen as potential HBA and prevents Reduction removes carbonyl oxygen as potential HBA and prevents

ionisationionisation• Esterification prevents ionisation, HBD interactions and may hinder HBA Esterification prevents ionisation, HBD interactions and may hinder HBA

by a steric effectby a steric effect


No ionic bonding possible

NHR2

binding site

C

O

O

Analogue

CH3

+

H-Bonding hindered

X

H

steric shield

C

O

O

Analogue

CH3

RC

OH

O

LiAlH4

H+ / R'OH RC

OR'

O

RCH2

OH

Ester

1o Alcohol

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2.8 SAR on Aromatic Rings and Alkenes2.8 SAR on Aromatic Rings and Alkenes

binding site binding site

Drug

Drug

R R

hydrophobichydrophobicregionregion

vdw

vdw

hydrophobichydrophobicpocketpocket

H2 / Pd/C

H2 / RaNiDrug Drug

H

R'H

R H

R'H

R

HH

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Possible effects on bindingPossible effects on binding

2.8 SAR on Aromatic Rings and Alkenes2.8 SAR on Aromatic Rings and Alkenes

binding sitehydrophobichydrophobicregionregion

binding site

hydrophobichydrophobicpocketpocket

Analogue

HH

Nofit

Analogue

R RHH

‘Buffers’

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• Acid chlorides Acid chlorides - too reactive to be of use - too reactive to be of use• Acid anhydrides- too reactive to be of use Acid anhydrides- too reactive to be of use • Alkyl halidesAlkyl halides -present in anticancer drugs to form covalent bonds with-present in anticancer drugs to form covalent bonds with

nucleophiles in target nucleophiles in target• Aryl halides Aryl halides -commonly present. Not usually involved in binding -commonly present. Not usually involved in binding

directlydirectly• Nitro groups Nitro groups -sometimes present but often toxic-sometimes present but often toxic• Alkynes Alkynes -sometimes present, but not usually important in binding -sometimes present, but not usually important in binding

interactions interactions• Thiols Thiols -present in some drugs as important binding group to -present in some drugs as important binding group to

transition metals (e.g. Zn in zinc metalloproteinases) transition metals (e.g. Zn in zinc metalloproteinases)• Nitriles Nitriles - present in some drugs but rarely involved in binding- present in some drugs but rarely involved in binding

• Functional groups may be important for electronic reasons Functional groups may be important for electronic reasons (e.g. nitro, cyano, aryl halides)(e.g. nitro, cyano, aryl halides)

• Functional groups may be important for steric reasons Functional groups may be important for steric reasons (e.g. alkynes)(e.g. alkynes)

2.9 Miscellaneous Functional Groups in Drugs2.9 Miscellaneous Functional Groups in Drugs

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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

Patrick An Introduction to Medicinal Chemistry 3/e Chapter 10 DRUG DESIGN:

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