1 MEDICINAL CHEMISTRY I (PharmD) 2012 Topic 3: Drug Design and Discovery Dr. Tareq Abu-Izneid & Dr....

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MEDICINAL CHEMISTRY I (PharmD) 2012

Topic 3: Drug Design and Discovery

Dr. Tareq Abu-Izneid&

Dr. Munjed [email protected]

mailto:[email protected]

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Resources• Text

Patrick, G.L., 4th edn., Part C (Chapters, 12, 13 and 14) Lemke, T.L., & Williams, D.A., 6th edn, Ch 1

Objectives Outline, describe & give examples of the 12 stages of

drug discovery & development process Drug Targets (Enzymes and receptors) Sources of Lead Compounds (Sources of drugs) Isolation and purification Structure determination Impact of the human genome project SAR and Pharmacophore

Optimisations of lead compound Optimising bonding interactions optimising pharmacokinetic properties

Prodrugs Aims Examples

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The Drug Discovery & Development Process

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Stages: 1) Identify target disease 2) Identify drug target 3) Establish testing procedures 4) Find a lead compound 5) Structure Activity Relationships (SAR) 6) Identify a pharmacophore 7) Drug design- optimising target interactions 8) Drug design - optimising pharmacokinetic properties 9) Toxicological and safety tests10) Chemical development and production11) Patenting and regulatory affairs12) Clinical trials


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1. Target Disease (Choosing a disease!) Priority for the Pharmaceutical Industry

• Can the profits from marketing a new drug outweigh the cost of developing and testing that drug?

Questions to be addressed

• Is the disease widespread? (e.g. cardiovascular disease, ulcers, malaria)

• Does the disease affect the first world? (e.g. cardiovascular disease, ulcers)

• Are there drugs already on the market?• If so, what are there advantages and disadvantages?

(e.g. side effects)

• Can one identify a market advantage for a new therapy?

Choosing which disease to tackle is a matter for a company’s market strategists!!

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2. Drug Targets (Receptor or Enzyme)

A) PROTEINS • Receptors (Agonist or antagonist)• Enzymes inhibitor (reversible or irreversible)• Transporters (Uptake inhibitors)• Ion channels (Blockers or openers)

B) LIPIDS• Cell Membrane Lipids (e.g. Polyenes antifungals)

C) NUCLEIC ACIDS (e.g. alkylating agents)• DNA• RNA

D) CARBOHYDRATES• Cell surface carbohydrates

An understanding of which biomacromolecules are involved in a particular disease state is clearly important!

This allows the drug designer to identify whether agonists or antagonists should be designed for a particular receptor or whether inhibitors should be designed for a particular enzyme!

Drug targets are most often proteins, but nucleic acidsmay also be attractive

targets for some diseases.

A bio(macro)molecule may be involved in a disease process, but to bea drug target it has to be validated. In other words shown to be criticalin the disease process.

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Between species: (Chemotherapy!)

• Antibacterial and antiviral agents• Identify targets which are unique to the invading pathogen• Identify targets which are shared but which are significantly different in

structure

Within the body:

• Selectivity between different enzymes, receptors etc.• Selectivity between receptor types and subtypes• Selectivity between isozymes• Organ selectivity

TARGET SELECTIVITY

2. Drug Targets (Receptor or Enzyme)

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• Tests are required in order to find lead compounds and for drug optimisation

• Tests can be in vivo or in vitro

• A combination of tests is often used in research programmes

3. Establish Testing Procedures

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Screening or assaying:

“The testing of a (series of) molecule(s) against a known biological target that correlates with a cellular or pharmacological activity is known as screening - e.g. enzyme inhibition or receptor binding”

Summary for the first three stages

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Pharmaceutical companies tend to concentrate on developing drug for diseases that are prevalent in the developed countries, and aim to produce compounds with better properties than existing drugs!

A molecule target is chosen which is believed to influence a particular disease when affected by a drug. The greater the selectivity that can be achieved, the less chance of side effects



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New projects can be divided into those which have “lead compounds” on which to base the design of novel analogues, and those which do not.

4. Find a lead compound

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A lead compound is: “a compound from a series of related compounds that has some of a desired biological activity.

This molecule can be characterized, and modified to produce another molecule with a better profile of wanted properties to unwanted side effects”

The level of activity and target selectivity are not crucial

Used as the starting point for drug design and development

A lead compound is a first foothold on the drug discovery ladder

It takes much more effort to make a lead compound into a drugCandidate

Found by design (molecular modelling or NMR) or by screening compounds (natural or synthetic)

4.1 Sources of Lead Compounds

A) The Natural World

B) The Synthetic World

C) The Virtual World

Plantlife (flowers, trees, bushes)

Micro-organisms (bacteria, fungi)

Animal life (frogs, snakes, scorpions)

Biochemicals (Neurotransmitters, hormones)

Marine chemistry (corals, bacteria, fish etc)

Chemical synthesis (traditional)Combinatorial synthesis

Computer aided drug design

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Existing drugs can be used as lead compounds for the design of a novel structure in the same therapeutic area.

Alternatively, the side effects of an existing drug can be enhanced to design novel drugs in a different therapeutic area?

4.2 Identification of Lead Compounds

A) Isolation and purification1) solvent-solvent extraction (partitioning!)2) chromatography (TLC, HPLC)3) crystallisation (based on solubility)4) distillation (based on differences in boiling point)

B) Structure determination5) NMR (1H, 13C, 2D) >>> (structure!) (Functional groups)6) Mass spectrum >>> (molecular weight or mass)7) Elemental analysis >>> percentage of different atoms in a

molecule)8) Infra red (IR)>>>(functional groups!)9) Ultra violet (UV)>>> (absorbance)

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4.1 Sources of Lead Compounds

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The isolation of many bioactive products from natural sources has led to the systematic screening of plant and animal extracts for activity.

Natural product screening

• Active Principle - a compound that is isolated from a natural extract and which is principally responsible for the extract’s pharmacological activity.

Often used as a lead compound.

PLANT EXTRACTS

• OPIUM - Morphine

• CINCHONA BARK - Quinine

• YEW TREE - Taxol

4.2.1 Lead Compounds from the Natural World

Problems with natural product screening:

• Isolation of an active component present in a very small amount can be problematic given a large amount of background “rubbish”

• The mixtures are often very complex and contain many large macromolecules. These can often “hide” biological activity

• Compound isolation and structure determination difficult

• Structures often complex, therefore difficult to synthesise and identify the pharmacophore.

WILLOW TREE - SALICYLIC ACID

COCA BUSH - COCAINE

Aspirin

Procaine

OH

O OHAceticanhydride O

O OH

CH3

O

N

Me

O

H

H

CO2Me

C

O

O

C

O

N

NH2

CH3

CH3

PLANT EXTRACTS

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ENDOGENOUS COMPOUNDS NATURAL LIGANDS FOR RECEPTORS

HO

HO

ADRENALINE

HN

Me

OH

HO

HO

OH

SALBUTAMOL

HN

Agonist

NH2

NH

HO

5-HYDROXYTRYPTAMINE

NMe2

NH

SUMATRIPTAN

SMeHN

O OAgonist

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5HT (serotonin natural agonist)

5HT (serotonin agonist)

Used for migraine headache

(adrenergic natural agonist) (β2 adrenergic agonist) Used for Asthma

The natural substrate for a receptor or enzyme can serve as a starting point for lead discovery. E.g. salbutamol, an analogue of the natural compound adrenaline, was developed to treat asthma.

O NH

OH

PROPRANOLOL

AntagonistHO

HO

ADRENALINE

HN

Me

OH

HNN

Me

S

HN NHMe

CN

CIMETIDINE

HNN

NH2

HISTAMINEAntagonist

ENDOGENOUS COMPOUNDS

NATURAL LIGANDS FOR RECEPTORS

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(adrenergic natural agonist) (β adrenergic antagonist)

(H2 antagonist)

VENOMS AND TOXINS

Captopril(anti-hypertensive)

H2N CH C

CH2

O

CH2

C

OH

O

NH

CH C

CH2

O

HN

N

C

O

NH

CH C

CH2

O

CH2

CH2

NH

C

NH2

NH

N

C

O

NH

CH C

CH2

O

CH2

C

NH2

O

HN CH C

CH

O

CH3

CH2

CH3

N

C

O

N

C OH

O

CH3

C

O

N

C OH

O

HS

Teprotide

Lead Compounds from the Natural World

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H2N S NH2

O

NN

NH2

O

PRONTOSIL

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4.2.2 Lead Compounds from the Synthetic World

S NH2

O

H2N

O

SULFANILAMIDE

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4.2.2 Lead Compounds from the Synthetic World

The Past

Lead Compound

Targets

Targets

Lead compounds

The Future

Lead Compounds 4.3 Impact of the human genome project

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• Advances in molecular biology techniques means making and isolating “large” amounts of proteins much easier nowadays.

• X-ray crystallography has developed so that the determination of the 3-D crystal structures of proteins and receptors is becoming easier.

• Coupled with advances in computing power and molecular modelling the so-called rational or structure-based drug design hasbeen advanced as “the way forward” in the search for new drugs.

4.4 Lead Compounds - Rational drug design

(molecular modelling)

The ability to crystallise a molecular target allows the use of X-ray crystallography and molecular modelling to design lead compounds which fit the relevant binding site

PROTEIN STRUCTURE

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4.4 Lead Compounds - de novo design (molecular modelling)

The ability to crystallise a molecular target allows the use of X-ray crystallography and molecular modelling to design lead compounds which fit the relevant binding site

The Design of Relenza (influenza neuraminidase inhibitor)

Relenza bound in the active site of influenza neuraminidase

Neuraminidase is an enzyme involved in the influenza virus cycle.

A screen of inhibitors of neuraminidase came up with a hit which was developed into a lead compound.

The X-ray crystal structure of the virus enzyme is known so a computational study has allowed the “docking” (superposition) of the lead structure into the

active site of the enzyme.

This study is directing optimization of the inhibitor structure through determination of the intermolecular forces between enzyme and inhibitor.

Important interactions between the guanidino group and influenza neuraminidase

The Design of Relenza



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5 & 6 Structure Activity Relationships (SAR) & Identifying Pharmacophore

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

in vitro - tests for binding interactions with target in vivo - tests for target binding interactions and/or pharmacokinetics

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

METHOD

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We have defined a lead compound as “a compound from a series of related compounds…...”. The question is therefore posed what are the essential structural elements for biological activity? >> (pharmacophore)

• Defines the important groups involved in binding

• Defines the relative positions of the binding groups

• Need to know Active Conformation

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Once a pharmacophore has been identified as series of relatedcompounds must be made to improve potency and reduce toxicity

Determination of a structure-activity relationship (SAR) is the process by which chemical structure is correlated with biological

Activity

5 & 6 Structure Activity Relationships (SAR) & Identifying Pharmacophore



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7. DRUG DESIGN - OPTIMISING BINDING INTERACTIONS

AIM - To optimise binding interactions with target

STRATEGIES • Vary alkyl substituents• Vary aryl substituents• Extension• Chain extensions / contractions• Ring expansions / contractions• Ring variation• Isosteres• Simplification• Rigidification

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

REASONS

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7.1 Vary Alkyl Substituents

Rationale : • Alkyl group in lead compound may interact with hydrophobic

region in binding site• Vary length and bulk of group to optimise interaction

ANALOGUE

C

CH3

CH3H3C

van der Waals interactions

LEAD COMPOUND

CH3

Hydrophobicpocket

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Rationale : Vary length and bulk of alkyl group to introduce selectivity

Fit

Fit

NCH3

N CH3 Fit

No Fit

StericBlock

N CH3

CH3

N

Binding region for N

Receptor 1 Receptor 2

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Example: Next....Selectivity of adrenergic agonists and antagonists for b-adrenoceptors over a-adrenoceptors

Salbutamol (Ventolin) (Anti-asthmatic)

Adrenaline

Propranolol(b-Blocker)

OH

O NH

CH3

CH3H

HOCH2

HO

HN

CCH3

OH

CH3

H

CH3

HO

HO

HN

CH3

OHH

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RECEPTOR

Rationale : To explore target binding site for further bindingregions to achieve additional binding interactions

7.2 Extension - Extra Functional Groups

Unusedbindingregion

DRUG

RECEPTOR

DRUGExtrafunctionalgroup

Binding regions

Binding group

DrugExtension

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Example : ACE Inhibitors

EXTENSION

Hydrophobic pocket

Bindingsite

NH

N

O CO2

O

O

CH3

Bindingsite

NH

N

O CO2

O

O

CH3

(I)

Hydrophobic pocket

Vacant

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7.2 Extension - Extra Functional Groups

Rationale : • Useful if a chain is present connecting two binding groups• Vary length of chain to optimise interactions

7.3 Chain Extension / Contraction

RECEPTOR

A BA B

RECEPTOR

Binding regions

Binding groupsA & B

Weakinteraction

Stronginteraction

Chain extension

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Bindinggroup

Bindinggroup

Example : N-Phenethylmorphine

Optimum chain length = 2

HO

O

HO

N (CH2)n

H

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7.3 Chain Extension / Contraction

N

N

7.4 Ring Variations

Example :

Improved selectivityvs. fungal enzyme

Antifungal agent

Cl

F

C

OHN

N

Structure I

Ringvariation

Cl

F

C

OHN

NN

UK-46245

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Rationale : Sometimes results in improved properties

Rationale : • Lead compounds from natural sources are often

complex and difficult to synthesise

• Simplifying the molecule makes synthesis of analogues easier, quicker and cheaper

• Simpler structures may fit binding site easier and increase activity

• Simpler structures may be more selective and less toxic if excess functional groups removed

7.5 Simplification

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Methods:• Retain pharmacophore • Remove unnecessary functional groups

OH

NHMe

OMe

HOOC

Ph

Cl

Drug

OH

NHMePh Drug

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7.5 Simplification

Excess ring

Methods:• Remove excess rings

Example

HO

O

HO

N CH3

HH

Morphine

Excess functional groups

HO

N CH3

HH

Levorphanol

HO

Me

Me

N CH3

HH

Metazocine

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7.5 Simplification

Methods:• Remove asymmetric centres

YN

X

Achiraldrug

YC

X Y

Achiraldrug

YC

X H

Chiraldrug Asymmetric centre

YC

X H

Chiraldrug Asymmetric centre

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7.5 Simplification

Pharmacophore

Example

• Important binding groups retained• Unnecessary ester removed• Complex ring system removed

COCAINE

N

H

O

Me

C

CO2Me

H

O

PROCAINE

C

NH2

O

O

Et2NCH2CH2

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7.5 Simplification

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7.5 Simplification

Disadvantages:

• Oversimplification may result in decreased activity and selectivity

• Simpler molecules have more conformations

• More likely to interact with more than one target binding site.

MORPHINE

SIMPLIFICATION

CC

C

CC

CO

N

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7.5 Simplification

Example of oversimplification

Simplification of opiates

7.6 De Novo Drug Design

Procedure• Crystallise target protein with bound ligand • (e.g. enzyme + inhibitor or ligand)• Acquire structure by X-ray crystallography• Identify binding site (region where ligand is bound)• Remove ligand• Identify potential binding regions in the binding site• Design a lead compound to interact with the binding site

• Synthesise the lead compound and test it for activity• Crystallise the lead compound with target protein and identify

the actual binding interactions• Structure based drug design 50

The design of novel agents based on a knowledge of the target binding site



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8. Pharmacokinetics – drug design

Aims:

• To improve pharmacokinetic properties of lead compound

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

enzymes)

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

through cell membranes / access to CNS / excretion rate)

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

targets

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

• Drugs must have both hydrophilic and lipophilic characteristics

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

Receptor interaction& water solubility

Crossesmembranes

+ H

HN N H

H

- H

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8. Pharmacokinetics – drug design

8.1.1 Vary alkyl substituents

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

hydrophobic balance of the structure• Larger alkyl groups increase hydrophobicity

Disadvantage: • May interfere with target binding for steric reasons

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

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

skeleton - full synthesis often required

8.1 Solubility and membrane permeability

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8.1.1 Vary alkyl substituents

Methylene 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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8.1.2 ‘Masking’ or removing polar groups

Rationale: • Masking or removing polar groups decreases polarity and

increases hydrophobic character

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

already (simplification strategy)• See also prodrugs

Methods:R OH R OMe

CH3I

R NHR

CH3COCl

R

HN

O

CH3

RC

OH

O

H+ / R'OH RC

OR'

O56


1.1.3 Adding polar groupsRationale:• Adding polar groups increases polarity and decreases

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

Disadvantage: • May 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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8.1.4 Vary pKa

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

Disadvantage:• May affect binding interactions

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

aromatic carboxylic acids

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Antithromboticbut too basic

Decreased basicityN locked into heterocycle

H2N NH

NH

O

N

O

N

N

(I)

amidine

N NH2

NH

O

N

O

N

N

PRO3112

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8.1.4 Vary pKa


Terminal amide

StericShield

8.2.1 Steric Shields

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

hydrolysis• Hinders attack by nucleophiles or enzymes

Blocks hydrolysis of terminal amide

Antirheumatic agentD1927

HSNH

HN CONHMe

O

O

C

NOO

H3C CH3CH3

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8.2 Drug stability

8.2.2 ‘Electronic shielding’ of NH2

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

reactive• Increases chemical and metabolic stability

ISOSTERE

H3CC

O

O O

C

O

H2NR R

ISOSTERE

NH

C

O

CH3H3C

C

O

OR R

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8.2 Drug stability

8.2.3 Stereoelectronic Effects

Rationale: • Steric and electronic effects used in combination• Increases chemical and metabolic stability

ortho Methyl groups act as steric shields &hinder hydrolysis by esterasesAmide more stable than ester (electronic effect)

Local anaesthetic(short duration)

PROCAINE

CH2N

O

O CH2CH2NEt2

LIDOCAINE

CH3

CH3

NH

C

CH2NEt2

O

8.2 Drug stability

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

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

Oral contraceptive - limited lifetime

8.2.5 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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8.2 Drug stability

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

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

Susceptible group

Unsusceptible group

8.2.6 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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8.2 Drug stability

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

SalbutamolSusceptible group

Unsusceptible group

8.2.7 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 65

8.2 Drug stability

metabolicallysusceptible

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

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

metabolic reactions

Example:Anti-arthritic agents

1.2.8 Introducing susceptible metabolic groups

CH2OH

CO2H

SO2Me

N

Cl

NL787257

SO2Me

N

Cl

N CH3L791456

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8.2 Drug stability

Example - varying substituents

• Fluconazole (Diflucan) - antifungal agent

Cl

Cl

C

OH NN

NNNN

UK-47265

Substituents variedLess toxic

F

F

C

OH NN

NNNN

Fluconazole

8.3 Reducing drug toxicity

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Example - varying substituent position

• Dopamine antagonists

Inhibits P450 enzymes

N

HN

ONC

HN

No inhibition of P450 enzymes

N

HN

O

HN

NC

68

8.3 Reducing drug toxicity



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Pro-drugs

70

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

Uses ...Aims.....(improving drug profile!)• Improving membrane permeability• Prolonging activity• Masking toxicity and side effects• Varying water solubility• Drug targeting• Improving chemical stability

8.5 Prodrugs

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8.5.1 Prodrugs to improve membrane permeability

8.5.1.1 Esters• Used to mask polar and ionisable carboxylic acids• Hydrolysed in blood by esterases• Used when a carboxylic acid is required for target binding• Leaving group (alcohol) should ideally be non toxic

Example:Enalapril for enalaprilate (antihypertensive)

O

NH

O

RO

CO2H

N

CH3

R=Et EnalaprilR=H Enalaprilit 72

Example:Candoxatril for Candoxatrilat (protease inhibitor)

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

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

Candoxatrilat

HN

O

OCO2H

OMe

HO

O

HN

O

OCO2H

OMe

O

O

Candoxatril

5-indanyl group

73


8.5.1.2 N-Methylation of amines

• Used to reduce polarity of amines• Demethylated in liver

Example:Hexobarbitone

N NH

Me

O O

O

Me

74


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

8.5.1.3 Trojan Horse Strategy

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

Example: Levodopa for dopamine

CH2

CH2

HONH2

HO HO

NH2

C

HO

CH2 CO2H

H

75


COOHH2N

L-Dopa

COOHH2N

Enzyme

Dopamine

H2N

Bloodsupply

Braincells

BLOOD BRAIN BARRIER

76


Example: Azathioprine for 6-mercaptopurine

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

Azathioprine• Slow conversion to 6-mercaptopurine• Longer lifetime

8.5.2 Prodrugs to prolong activity

N

H

SH

NN

N

N

NN

N

S N

N

O2N

Me

H

77

8.5.2.1 Mask polar groups

• Reduces rate of excretion

Example: Valium for nordazepam

Valium Nordazepam

N-DemethylationN

NO

Me

Cl Cl

N

HO

N

78


Example: Hydrophobic esters of fluphenazine (antipsychotic)

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

S

HN CF3

N

N

O (CH2)8CH3

O

fatty ester

79


8.5.2.2 Add hydrophobic groups

Example:Aspirin for salicylic acid

8.5.3 Prodrugs to mask toxicity and side effects

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

Aspirin• Phenol masked by ester• Hydrolysed in body

OH

CO2H O

CO2H

O

H3C

80

• Mask groups responsible for toxicity/side effects• Used when groups are important for activity

8.5.4 Prodrugs to lower water solubility

Example: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

81

• Used to reduce solubility of foul tasting orally active drugs • Less soluble on tongue• Less revolting taste

8.5.5 Prodrugs to increase water solubility

Succinate ester

O2N

OH

HN

O

O

Cl

ClH

H

O

OHO

Esterase

Chloramphenicol

O2N

OH

HN

O

OH

Cl

ClH

H

82

• Often used for i.v. drugs • Allows higher concentration and smaller dose volume• May decrease pain at site of injection

Example:Succinate ester of chloramphenicol (antibiotic

Example: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

83

8.5.5 Prodrugs to increase water solubility

8.5.6 Prodrugs to increase chemical stability

Example:Hetacillin for ampicillin

• Ampicillin is chemically unstable in solution due to the a-NH2 group attacking the b-lactase ring

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

Example: Carbidopa

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

8.6.1 Sentry Drugs

Other examples: Clavulanic acid and candoxatril

L-DOPA DOPAMINEENZYME

INHIBITION

CARBIDOPA

CNHNH2

HO

Me

HO

CO2H

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Example: Adrenaline and procaine (local anaesthetic)

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

8.6.2 Localising drugs to a target area

8.6.3 Increasing absorption

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

analgesics• Leads to faster pain relief

Example: Metoclopramide

Cl

NH2

OCH3

OHN

N(Et)2

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Structure based drug design

Procedure:• Crystallise target protein with bound ligand

(e.g. enzyme + inhibitor or ligand)• Acquire structure by X-ray crystallography• Identify binding site (region where ligand is bound)• Identify binding interactions between ligand and target

(modelling)• Identify vacant regions for extra binding interactions

(modelling)• ‘Fit’ analogues into binding site to test binding capability

(modelling)87

Strategy:Carry out drug design based on the interactions between the lead compound and the target binding site



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Drug MetabolismIdentification of drug metabolites in test animals

Properties of drug metabolites

ToxicologyIn vivo and in vitro tests for acute and chronic toxicity

PharmacologySelectivity of action at drug target

FormulationStability testsMethods of delivery

9.1 Preclinical trials



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Case Study - Development of Design of Antihypertensives - ACE inhibitors

• ACE = Angiotensin converting enzyme• Angiotensin II

- hormone which stimulates constriction of blood vessels - causes rise in blood pressure

• ACE inhibitors - useful antihypertensive agents• ACE - membrane bound zinc metalloproteinase not easily

crystallised• Study analogous enzyme which can be crystallised

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu

Angiotensin I

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe

Angiotensin II

His-LeuACE

+

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Design of Antihypertensives - ACE inhibitors

Natural Substrate

R NH

O

O

O

Zn2+

S1' pocket

NH2

H2N

145

Zn2+

Hydrolysis

R

O

O

H2NO

O

S1' pocket

NH2

H2N

145

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Carboxypeptidase mechanism

No hydrolysisL-benzylsuccinic acid

OO

O

O

Zn2+

S1' pocket

NH2

H2N

145

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Inhibition of carboxypeptidase

Teprotide

Glu-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro

L-Benzylsuccinic acid

OH

O

O

OH

N

O

HO

O

CO2H

Succinyl proline

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Lead compounds for ACE inhibitor

Proposed binding mode

Succinyl prolineN

O

O

O

CO2

Zn2+

H2N

H2N

S1' pocket

S1 pocket

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Extension and bio-isostere strategies

N

O

HS

CO2

CH3

S1' pocket

S1 pocket

Zn2+

H2N

H2N

N

O

O

OH

CO2H

N

O

O

OH

CO2H

CH3

N

O

HS

CO2H

CH3

Captopril

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Extension strategies

Inhibitor

NH

N

O CO2

O

O

CH3

S1' pocket

S1 pocket

Zn2+

H2N

H2N

NHN

O CO2H

O

O

NH

N

O CO2H

O

O

CH3

Enalaprilate

NH

N

O CO2H

O

O

CH3

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1 MEDICINAL CHEMISTRY I (PharmD) 2012 Topic 3: Drug Design and Discovery Dr. Tareq Abu-Izneid & Dr....

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Transcript of 1 MEDICINAL CHEMISTRY I (PharmD) 2012 Topic 3: Drug Design and Discovery Dr. Tareq Abu-Izneid & Dr....