03 sar pharmacophore identification drug optimization

STRUCTURE-ACTIVITY RELATIONSHIP, AND DRUG OPTIMIZATION STRATEGIES

PHARMACEUTICAL CHEMISTRY 129AY 2010-2011

OBJECTIVES

At the end the student should be able to:

Know the concept of structure-activity relationships and pharmacohphores;

Know the different design strategies employed to improve the overall pharmacodynamic, pharmacokinetic and toxicity profile of a drug;

Understand how these design strategies render the drugs safer and more effective;

Appreciate the efforts of medicinal chemists in giving us insight on the strategies in designing drugs to make them safer and more effective.

STRUCTURE-ACTIVITY RELATIONSHIPS

STRUCTURE ACTIVITY RELATIONSHIPS (SAR)

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

AIM FOR STUDYING SARS

STUDYING SAR

Target

Lead Compound

X-ray crystallography

Crystallized structure

In silico analysis

Computer generated analogue

Lab Synthesis of analogues

(Combinatorial Chemistry)

In vivo

Crystal structure not

possible

In vitro

Active in vivo and in vitro

Allows identification of important groups involved in

binding

Allows identification of the pharmacophore

Gives information on the modifications that improves binding and pharmacokinetic

profile

NOTES ON ANALOGUES

Modifications may disrupt binding by electronic/ steric effect

Easiest to make are those made from lead compound

Possible modifications may depend on other groups present

Some may have to be made by a full synthesis

HBD

X

Binding site

X= N or O

OH

Drug

O

H

Drug

X

Binding site

H

HBA

ALCOHOLS AND PHENOLS

POSSIBLE BINDING INTERACTIONS

POSSIBLE ANALOGUES

H-Bonding

R OH

Ether

R OMeCH3I

EsterCH3COCl

RO

O

CH3

AlkaneCH3SO2Cl

R SO

O

CH3

O

LiAlH4R H

Example: ether

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


• Increased resistance to metabolism• Decreased excretion• Increased absorption

POSSIBLE EFFECT OF ANALOGUE IN BINDING

POSSIBLE EFFECTS ON PHARMACOKINETIC PROFILE

POSSIBLE EFFECT OF ANALOGUES ON BINDING


Example: ester

X= N or OX

Binding site

H

Electronic factor Steric Factor

steric shield

X

Binding site

H

OC

Ester analogue

CH3

O

OC

CH3

O

+ OC

Ester analogue

CH3

O

• Increased susceptibility to metabolism• Increased absorption


• amine is ionised

HBD

X

Binding site

X= N or OCO2

-

Binding site

NH2R

Drug

+ NH

Drug

R2

+

AMINES


H-Bonding

Ionic Bonding



• Free base

AMINES


HBD

X

Binding site

X= N or O

X

Binding site

H

HBA

NH

Drug

RN

R

Drug

H

H-Bonding

1o amines

POSSIBLE ANALOGUES

2o aminesR2 NH

CH3COCl R2N

O

CH3

R NH2

CH3COCl

R

HN

O

CH3

R NHRCH3COCl

R

RN

O

CH3R NHR

CH3

VOC-Cl

O CH3

O

Demethylation

2o amine

3o amine with methyl substituent

2o amide

3o amide

3o amide

AMINES

CO2-

Binding site

No interaction

N CH3

O

R

Amide analogue


AMINES

• Increased resistance to metabolism• Increased excretion• Increased absorption


• Full synthesis of 1o-3o amines and amides

CO2-

Binding site

Ionic bonding

NR3

Drug

+

NR3

Drug

+

Induced dipole interactions

Binding site

δ +

δ -


POSSIBLE ANALOGUES

QUATERNARY AMMONIUM SALTS

Binding site (X= N or O)

XH

H-Bonding

HBA

ODrug

Binding site

ODrug


POSSIBLE ANALOGUES

R R'

O NaBH4 or LiAlH4

R R'

HO H

Ketone

Planar sp2 carbon centre

2o AlcoholTetrahedral sp3 carbon centre

Dipole-dipole interactions

ALDEHYDES AND KETONES

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


Change in stereochemistry

Binding site

XHH

OH

Alcoholanalogue

(X= N or O)

ALDEHYDES AND KETONES

• Increased susceptibility to metabolism• Increased excretion• Decreased absorption



X= N or OX

Binding site

H

OC

CH3

O

X

Binding site

H

O C CH3

O

ESTERS

POSSIBLE ANALOGUES

NaOH RC

OH

O

CH3HO+

Carboxylic Acid

Alcohol

LiAlH4 RCH2

OH

1o Alcohol

RC

O

O

CH3=

ESTERS

ESTERS

HydrolysisLoss of activity due to loss of other functional groups

only suitable for simple esters

• Increased resistance to metabolism• Increased excretion• Decreased absorption


POSSIBLE EFFECTS OF ANALOGUE ON BINDING

ESTERS

Reduction to alcoholcan establish importance of the carbonyl oxygen

reaction can be difficult to do if other labile functional groups are present



POSSIBLE EFFECTS OF ANALOGUE ON BINDING

C O

O

R CO

O

R C OH

O

Prodrug

esterase

Drug

ESTERS

Fattybarrie

r

OC

R

O

OC

R

O

OH

Prodrugesterase

Drug


X

H


X

HBA HBDN

Drug

H

O

R

N

Drug

H

O

R

H-bonding

AMIDES


RC

HN

OR'

LiAlH4

NaOH

NaH/ CH3I

RC

OH

OR'H2N+

Carboxylic acid

Amine

RCH2

NH2

1o Amine

RC

CH3N

OR'

3o

Amide

POSSIBLE ANALOGUES

AMIDES

POSSIBLE EFFECTS OF ANALOGUES IN BINDING

AMIDES

Hydrolysismay lead to a loss of activity due to loss of other functional groups

only suitable for simple amides

• Increased susceptibility to metabolism• Increased excretion• Decreased absorption


POSSIBLE EFFECTS OF ANALOGUES IN BINDING

AMIDES

Reduction to amineremoves carbonyl group can establish importance of the

carbonyl oxygenreaction can be difficult to do if

other labile functional groups are present



No binding as HBD

X

N

CH3

O

R

Analogue

binding site

Binding of O as HBA hindered

XH

N

CH3

R

O

steric shield

Analogue

POSSIBLE EFFECTS OF ANALOGUES ON BINDING

AMIDES


XHHBA

XH

HBAC

OH

DrugO

C

OH

DrugO

X

HC

O

DrugO

HBD

H-bonding


CARBOXYLIC ACIDS

as free acid


XHHBA

Binding site

NHR2

+

OC

O

Drug

- OC

O

Drug

-

H-bonding Ionic bonding

CARBOXYLIC ACIDS

as carboxylate ionPOSSIBLE BINDING INTERACTIONS

POSSIBLE ANALOGUES

RC

OH

OLiAlH4

H+ / R'OH RC

OR'

OEster

RCH2

OH 1o Alcohol

CARBOXYLIC ACIDS

No ionic bonding possible

NHR2

binding site

C

O

O

Analogue

CH3

+

H-Bonding hindered

XH

steric shield

C

O

O

Analogue

CH3


CARBOXYLIC ACIDS

binding site binding site

Drug

Drug

R R

hydrophobicregion

vdw

vdw

hydrophobicpocket


H2 / RaNiDrug Drug

H2 / Pd/CH

R'H

R H

R'H

RHH

POSSIBLE ANALOGUES

AROMATIC RINGS AND ALKENES

binding sitehydrophobicregion

binding site

hydrophobicpocket

Analogue

HH

Nofit

Analogue

R RHH

‘Buffers’


AROMATIC RINGS AND ALKENES

• Easiest alkyl groups to vary are substituents on heteroatoms

• Vary length and bulk of alkyl group to test space available

POSSIBLE ANALOGUES

Drug

Drug

Drug

Analogue

Analogue

Analogue

N CH3

VOC-ClN H

R'XN R'

HBr R'X

O

CH3O

H

O

R'

Hydrolysis R'OH

C

OCH3C

OH

O O H

C

OR'

O

ALKYL GROUPS

hydrophobic slot

binding site

Drug

CH3

van der Waalsinteractions

binding site

hydrophobic ‘pocket’

Drug

CH3CH3H3C


ALKYL GROUPS

MISCELLANEOUS FUNCTIONAL GROUPS IN DRUGS

Functional Group

Notes/Comments

Acid chlorides too reactive to be of use

Acid anhydrides too reactive to be of use

Alkyl halides present in anticancer drugs to form covalent bonds with nucleophiles in target

Aryl halides commonly presentnot usually involved in binding directly

Nitro groups sometimes present but often toxic

Alkynes sometimes presentnot usually important in binding interactions

Thiols present in some drugs as important binding group to transition metals (e.g. Zn in zinc metalloproteinases)

Nitriles present in some drugs but rarely involved in binding

PHARMACOPHORE

PHARMACOPHORE

IUPAC definition:

“..the ensemble of a steric and electronic features that is necessary to ensure the optimal supramolecular interaction with a specific biological target structure and to trigger (or block) its biological response.”

PHARMACOPHORE

Highest common denominator of a group of ligands exhibiting a similar biologic effect

Summarizes the important binding groups: required for activityRelative positions in space with respect to each

IMPORTANCE OF PHARMACOPHORE CONCEPT

PHARMACOPHORE-BASED LIGAND DESIGN

NH

CH3

CH3

OH OH

PHARMACOPHORE-BASED LIGAND DESIGN

Applied in 3 domains:

1. Definition of relevant pharmacophoric features in a drug molecule

necessary to achieve a certain biological effect and to establish clear SARs

2. Scaffold hopping detecting molecules with different scaffolds (novel

chemotypes) by virtually screening large compound libraries

3. Prediction of pharmacological profiles for lead structures in silico

to predict unwanted side effect in very early stages of the drug discovery process

to reduce the risk of late failure of drug candidates

PHARMACOPHORE MODELING

4 steps in development

1.selection of a set of active ligands known to bind to the same target (same binding site)

2.Conformational analysis for all ligands

3.assignment of pharmacophoric features

4.molecular superimposition of the ligand conformations to develop a common 3D pharmacophore

Problems with Pharmacophore-Based Modeling• Unavoidable emphasis on

functional groups as the crucial binding groups

• The strength of binding of the target to the drug cannot be taken into account

DRUG OPTIMIZATION STRATEGIES

IMPROVEMENT OF DRUG-TARGET INTERACTION


IMPROVEMENT OF DRUG-TARGET INTERACTION

Homologous Series Vinylogues and Benzologues Isosteres and Bioisosteres Ring Transformations Conformational Restrictions Twin Drug Approach

HOMOLOGOUS SERIES

1. Monoalkylated Derivatives

2. Cyclopolymetheylenic Compounds

3. Open, Difunctional, Polymethylenic

4. Substituted Cationic Heads

HOMOLOGOUS SERIES

Chain Extension

Chain Contractio

n

Monoalkylated Derivatives

HOMOLOGOUS SERIES

Varying of length and bulk allows probing the depth and width of a hydrophobic pocket in the drug target

binding site

Drug

CH3CH3

H3C

binding site

hydrophobic ‘pocket’

Drug

CH3

HOMOLOGOUS SERIES

Larger alkyl groups often confer selectivity to target

Substituted Cationic Head

VINYLOGUES AND BENZOLOGUES

VINYLOGUES AND BENZOLOGUES

1. Vinylogue2. Ethynologue3. Benzologue

ISOSTERES AND BIOISOSTERES

Classical Isosteresatoms/functional groups with similar size, polarity, electronic distribution and bonding

NH

NH

O

O NH

NH

O

O

F


Non-Classical Isosteresdoes not obey the steric and electronic rules used to define classical isosteres but have the same physical and chemical properties

S

NH NH2

N

NH NH2

N

NH NH2

N+

O-

O

N

NH NH2

SO

O

NH2


Bioisosteresgroup that can be used to replace a functional group while retaining the desired biological activity

N

CH3

CH3CH3

OCH3

O

+ N

CH3

CH3CH3

ONH2

O

+

Towards receptor: BIOISOSTERE

Towards AcHE: NOT A BIOISOSTERE

RING TRANSFORMATIONS

Ring Opening

Ring Closure


Ring Expansion/ Contraction

NH

O O-

N

N

OO-O

N

N

O O-O

NH

OO-

Click icon to add picture

VARIATION OF RING SUBSTITUENTS• Steric hindrance• hydrophobic

properties• Electronic properties

OH

Y

Y

OH



“Benzo Cracking”

Restructuring of Ring System


CONJUNCTIVE APPROACH Addition of another

functional group to the lead compound

To probe extra binding interactions with the target

Effects: Frequently causes the

convertion of an agonist to an antagonist

Can cause increase in activity and selectivity of drug to its target

O

N

O

CH3

ONH

O-

O-

extension

O

N

O

CH3

ONH

O-

O-

RING TRANSFORMATION

CONJUNCTIVE APPROACH


DISJUNCTIVE APPROACH

N

HO

O

O

OHCH3

N

H

O

O

CH3

CH3

Cocaine

Procaine

Advantages

More flexible Can bind differently to targets May result to reduced activity May result to reduced

selectivity May lead to increased side

effects

Disadvantages

Easier, quicker, cheaper to synthesize

CONFORMATIONAL RESTRICTIONS

Incorporation of Rigid Functional Group

NH NH

NH2

N

N

O

O

O

OH

NH NH

NH2

N

N

O

O

O

OH

N

N

N

O

O

O

OHO

CH3

NH

NH2

Flexible chain

RigidRigid

CONFORMATIONAL RESTRICTIONS

DisadvantagesMore complicated to synthesize

No guarantee of retention of active conformation

A rigid molecule may no longer bind to the target if it changed its shape as a result of mutation

CONFORMATIONAL CONSTRICTIONS

O

NH

NS

O

O

F

F

F

Favors active conformation of

target

O

NH

NS

O

O

F

F

F

CH3H

Steric clash

O

NH

NS

O

O

F

F

F

CH3

H

Rejects active conformation of

target

TWIN DRUG APPROACH

Strategies

TWIN DRUG APPROACH

Combination Mode

TWIN DRUG APPROACH

Symbiotic Approach

IMPROVEMENT OF PHARMACOKINETIC PROPERTIES


IMPROVEMENT OF PHARMACOKINETIC PROPERTIES

Improving Absorption Manipulation of Metabolic

Susceptibility Selective Targeting Drug Alliances Prodrugs and Bioprecursors

IMPROVING ABSORPTION

Decrease PolarityVariation pKaBioisosteres Replacement

IMPROVEMENT OF ABSORPTION

Decreasing PolarityMasking of polar functional groupsAddition of alkyl group to the

carbon skeletonMethylene shuffle

CH3

N

NHN

N

O

CH3

CH3

S OO

N

N

CH3

methylene shuffle

CH3

N

NHN

N

O

CH3

S OO

N

N

N

CH3

CH3

N

NHN

N

O

S OO

N

N

CH3

N

CH3


Variation of pKaPreferred pKa: 6-9Variation of N-alkyl substituents

Extra or larger - increases electron-donating effect but it also increases steric bulk

“wrapping up” N within a ring

Reduced basicity

Improved absorption

NH2 NH

O

NH

CH3

N

O

N

N

N NH2

O

NH

CH3

N

O

N

N


Variation of pKaVariation of

Aromatic substituentsAddition of

electron-donating or electron-withdrawing substituents

Weak base Destabilized

CH3

CH3

NHCH3

N+O

-

O CH3

CH3

NH2+ CH3

N+O

-

O

H+

Cl

CH3

CH3

NHCH3

Cl

CH3

CH3

NH2+ CH3

H+

INCREASING ABSORPTION

Bioisosteres Replacement

O

O

Drug

H

NN

NN

Drug

H

• Ionized at pH 7.4• More lipophilic• Resistant to metabolic

reactions that degrade carboxylic acids

INCREASING RESISTANCE TO CHEMICAL AND ENZYMATIC DEGRADATION

Steric ShieldsUsually done to protect amides and esters

from hydrolysis

NO O

NH

SH

O

NH

CH3

CH3

NH

OCH3 CH3

CH3

O

NHCH3


Electronic Effect of Bioisosteres Replacement of the metabophore without

affecting the pharmacophore

S

N

NH

OSH H

OOH

O CH3

OO

cephalothin

S

N

NH

OSO H

OOH

O NH2

OO

CH3

cefuroxime


Stereoelectronic Modifications

O

O

NH2

NCH3

CH3

NHC

NH2 CH3

CH3

O

N

CH3

CH3

procaine lidocaine


Metabolic Blockers

OO

CH3

CH3

OCH3

H

H

H

CH3

O

OO

CH3

CH3

OCH3

H

H

H

CH3

O

CH3

OO

CH3

CH3

OCH3

H

H

H

CH3

O

OH

Megestrol acetate

Metabolic oxidation

Metabolic oxidation


Removal of Susceptible Groups

S

O

O

NHO

NH

CH3

CH3 S

O

O

NHO

NH

CH3

Cl

tolbutamide chlorpropramide

OH

OH


Group Shift

OH

OH

NH2

OH H

Noradrenaline

Salbutamol

CH2

OH

OH

NH

CH3

CH3CH3

OH H

• May render the molecule unrecognizable to both the target and metabolic enzyme

OH

OH

NH

CH3

CH3CH3

OH H

OH

OH

COMT

O

OH

CH3

NH

CH3

CH3CH3

OH H

ACTIVE

INACTIVE


Ring Variation

Cl

Cl

N

N

O

SCl

F

F

N

N

NN

N

N

OH

Tioconazole Fluconazole

DIMINISHING RESISTANCE TO DRUG METABOLISM

Introduction of Metabolically Susceptible Groups

N

N

SO

OCH3

Cl

N

N

SO

OCH3

Cl

CH3

O

OH

OH


Self-Destruct DrugsHalf-life is controlledChemically stable under one set of condition but becomes unstable and spontaneously degrades under another set of conditions

Advantage:inactivation does not depend on the

activity of metabolic enzymes, which could vary from patient to patient


N+

O

O

H

CH3R

H

NCH3

O

O

CH3

CH3

O

O

O

O

CH3

CH3

O

O

NCH3

O

O

CH3

O

CH3

O

CH3CH3

+ +

Atracurium

-H+

N

CH3

CH2O

O

H

R

+

SELECTIVE TARGETING

Targeting Tumor CellsTargeting Gastroinstestinal Tract Infections

Targeting Peripheral Regions rather than the Central Nervous System

SELECTIVE TARGETING

Mann ,J. 2002. Natural products in cancer chemotherapy: past, present and future Nature Reviews Cancer 2, 143-148 [online].Accessed [25 January 2009]

SELECTIVE TARGETING

Targeting Gastroinstestinal Tract Infections

ON

CH3NHS

O

O

NH2

ON

CH3N-

S

O

O

NH2

pKa = 6.0

SELECTIVE TARGETING

Targeting Peripheral Regions Rather than the Central Nervous System

N+

CH3

CH3

CH3

O

H

O

OH N

CH3

O

H

O

OHBr-

Ipatropium bromide atropine

CNS SIDE EFFECTS

DRUG ALLIANCES

Sentry DrugsLocalizing the Area of Activity of a Drug

Increasing Absorption

SENTRY DRUGS

Administration of a second drug alongside the principal drug

The second drug usually inhibits the enzyme that metabolizes the principal drugAmoxicillin + Clavulanic AcidLevodopa + Carbidopa

LOCALIZING THE AREA OF ACTIVITY OF A DRUG

Epinephrine + Procaine

Constricts blood vessels in the

vicinity of injection

Distribution throughout the

body is prevented

Prolonged anaesthetic activity

ADJUVANTS

increases gastric motilityIncreases absorption

O NHN

CH3

CH3

OCH3

Cl

NH2

Metoclopramide

PRODRUGS APPROACH

IMPROVING PHARMACOKINETIC PROFILE

PRODRUGS

More appropriatelydrug latentation

Intentional prodrug designThe chemical modification of a

biologically active compound to form a new compound, that upon in vivo enzymatic attack, will liberate the parent compound

2 main classes:BioprecursorsCarrier Prodrugs

CARRIER PRODRUGS

Criteria for Well-designed Carrier Prodrug:1.The linkage between the drug substance and the transport

moiety is usually a covalent bond.2.As a rule the prodrug is inactive or less active than the parent

compound. 3.The linkage between the parent compound and the transport

moiety must be broken in vivo.4.The prodrug, as well as the in vivo released transport moiety,

must be non-toxic.5.The generation of the active form must take place with rapid

kinetics to ensure effective drug levels at the site of action and to minimize either direct prodrug metabolism or gradual drug inactivation.

APPLICATIONS OF PRODRUG DESIGN

APPLICATIONS OF CARRIER PRODRUGS

Improvement of Membrane PermeabilityProlonging of Drug ActivityMasking of Toxicity and Side EffectsLowering Water SolubilityImprovement of Water SolubilityTargeting of DrugsIncreasing Chemical StabilityActivation by External Influence

IMPROVEMENT OF MEMBRANE PERMEABILITY

EstersN-methylationTrojan horse approach for carrier proteins


EstersNot all are hydrolyzed efficientlyAddition of e-withdrawing groups

O

OR F

FF

O

OHR

+

O-

F

FF

O

OR CH3+

O

OHR CH3O-


N-methylation

NHN

CH3

O

O O

CH3 NHNH

CH3

O

O Ometabolism

hexobarbitone


Trojan horse approach

O

OH

NH2OH

OH

Amino acid

transporter

levodopa

Blood brain barrier

BLOOD

BRAIN

C OO

decarboxylase

NH2

OH

OH

dopamine

PROLONGING OF DRUG ACTIVITY

For sustained level of drug for long period of time

NH

S

F

FF

N

N

OO

CH3

Fatty ester

Fluphenazine decanoate

MASKING OF TOXICITY AND SIDE EFFECTS

OP

NH

O

N

Cl

Cl

OP

NH

O

N

Cl

Cl

OH

OP

NH2

O

N

Cl

Cl

O

OH P

NH2

O

N

Cl

ClCH2

H

O

cyclophosphamide 4-hydroxycyclophosphamide

aldophosphamidephosphoramide mustard

ACTIVE

REDUCING TOXICITY

Making drug resistant to metabolismAromatic nitro groupsAromatic aminesBromo arenesHydrazinesHydroxylaminesPolyhalogenated compounds

Variation of apparently harmless constituents

Variation of position of substituents

LOWERING WATER SOLUBILITY

R = - H

ChloramphenicolR = - CO(CH2)14CH3 Chloramphenicol palmitate

N+ O

-O

O

OHNH

O

Cl

Cl

R

IMPROVEMENT OF WATER SOLUBILITY

To enable infusion of a drug in higher concentration but smaller volume

R = - H

CHLORAMPHENICOL

R = - CO(CH2)2COOH

CHLORAMPHENICOL SUCCINATE

N+ O

-O

O

OHNH

O

Cl

Cl

R

TARGETING OF DRUGS

NN

N

NO

H H

NH4+++ H

+ + OH2

NN

N

N

INFECTED URINARY TRACT

BLOOD

STABLE AT pH > 5

Methenamine

INCREASING CHEMICAL STABILITY

N

S

OOH

CH3

CH3

NNH

O

CH3 CH3

O

N

S

OOH

CH3

CH3

NHNH2

O

O

O

CH3 CH3

+

Hetacillin

NH

S

OOH

CH3

CH3

NHNH2

O

OH

O

ampicillin

END OF LECTURE

03 sar pharmacophore identification drug optimization

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