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    Drug Design Notes

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    DrHamad
    This document discusses strategies for drug design and optimization. It covers improving pharmacokinetic properties like solubility, permeability, stability and targeting through various chemical modifications. Some key strategies discussed include: 1) Varying alkyl groups to change hydrophilic/lipophilic balance. 2) Adding or removing polar groups to increase or decrease solubility. 3) Introducing groups to block susceptible metabolic sites and increase stability. 4) Shifting positions of metabolically labile groups or introducing groups to control metabolism. 5) Linking drugs to targeting moieties like monoclonal antibodies to selectively deliver drugs to diseased cells.

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    Drug Design Notes

    Uploaded by

    DrHamad
    526 views38 pages
    This document discusses strategies for drug design and optimization. It covers improving pharmacokinetic properties like solubility, permeability, stability and targeting through various chemical modifications. Some key strategies discussed include: 1) Varying alkyl groups to change hydrophilic/lipophilic balance. 2) Adding or removing polar groups to increase or decrease solubility. 3) Introducing groups to block susceptible metabolic sites and increase stability. 4) Shifting positions of metabolically labile groups or introducing groups to control metabolism. 5) Linking drugs to targeting moieties like monoclonal antibodies to selectively deliver drugs to diseased cells.

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    This document discusses strategies for drug design and optimization. It covers improving pharmacokinetic properties like solubility, permeability, stability and targeting through various chemical modifications. Some key strategies discussed include: 1) Varying alkyl groups to change hydrophilic/lipophilic balance. 2) Adding or removing polar groups to increase or decrease solubility. 3) Introducing groups to block susceptible metabolic sites and increase stability. 4) Shifting positions of metabolically labile groups or introducing groups to control metabolism. 5) Linking drugs to targeting moieties like monoclonal antibodies to selectively deliver drugs to diseased cells.

    Copyright:

    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    526 views38 pages

    Drug Design Notes

    Uploaded by

    DrHamad
    This document discusses strategies for drug design and optimization. It covers improving pharmacokinetic properties like solubility, permeability, stability and targeting through various chemical modifications. Some key strategies discussed include: 1) Varying alkyl groups to change hydrophilic/lipophilic balance. 2) Adding or removing polar groups to increase or decrease solubility. 3) Introducing groups to block susceptible metabolic sites and increase stability. 4) Shifting positions of metabolically labile groups or introducing groups to control metabolism. 5) Linking drugs to targeting moieties like monoclonal antibodies to selectively deliver drugs to diseased cells.

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    You are on page 1of 38

    Topic 7.

    2
    INTRODUCTION TO DRUG
    DESIGN
    Chapter 11 Patrick

    Contents
    Part 1: Sections 11.1 11.4
    1. Pharmacokinetics drug design
    1.1. Solubility and membrane permeability
    1.1.1.
    Vary alkyl substituents
    1.1.2.
    Masking or removing polar groups
    1.1.3.
    Adding polar groups
    1.1.4.
    Vary pKa
    1.2. Drug stability
    1.2.1.
    Steric Shields
    1.2.2.
    Electronic shielding of NH2
    1.2.3.
    Stereoelectronic Effects
    1.2.4.
    Bio-isosteres
    1.2.5.
    Metabolic blockers
    1.2.6.
    Remove / replace susceptible metabolic groups
    1.2.7.
    Shifting susceptible metabolic groups
    1.2.8.
    Introducing susceptible metabolic groups
    1.2.9.
    Introducing chemically susceptible groups
    1.3. Drug targeting
    1.3.1.
    Linking a biosynthetic building block
    1.3.2.
    Linking drugs to monoclonal antibodies
    1.3.3.
    Targeting gut infections
    1.3.4.
    Targeting peripheral regions over CNS
    1.4. Reducing drug toxicity

    Drug design and development


    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 tests
    10) Chemical development and production
    11) Patenting and regulatory affairs
    12) Clinical trials

    1. 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)

    1. Pharmacokinetics drug design

    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 pKas 6-8

    +H
    N

    -H
    Crosses
    membranes

    Receptor interaction
    & water solubility

    1.1 Solubility and membrane permeability


    1.1.1 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

    1.1 Solubility and membrane permeability


    1.1.1 Vary alkyl substituents
    Methylene Shuffle!
    CH3

    CH3
    N

    HN

    Extra bulk
    CH3

    O S

    HN

    CH3
    O

    CH3

    O S

    HN

    N
    N

    CH3

    Methylene
    shuffle

    H3C
    O S

    CH3

    CH3

    Viagra
    H3C

    UK343664

    1.1 Solubility and membrane permeability


    1.1.2 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
    CH I
    3

    OH

    OMe

    Methods:
    H
    N

    CH3COCl
    R

    NHR

    CH3

    R
    O

    OH
    C
    O

    H+ / R'OH

    OR'
    C
    O

    1.1 Solubility and membrane permeability


    1.1.3 Adding polar groups
    Rationale:
    Adding polar groups increases polarity and decreases hydrophobic
    character
    Useful for targeting drugs vs. gut infections
    Useful for reducing CNS side effects
    Cl

    N
    N

    H
    C

    N
    N

    N
    OH

    Cl

    Cl

    Tioconazole
    Antifungal agent with poor
    solubility - skin infections only

    Disadvantage:
    May introduce unwanted side effects

    Fluconazole
    Systemic antifungal agent
    improved blood solubility

    1.1 Solubility and membrane permeability


    1.1.4 Vary pKa
    Rationale:
    Varying pKa alters percentage of drug which is ionized
    Alter pKa to obtain required ratio of ionised to unionised drug
    Method:
    Vary alkyl substituents on amine nitrogens
    Vary aryl substituents to influence aromatic amines or aromatic
    carboxylic acids
    Disadvantage:
    May affect binding interactions

    1.1 Solubility and membrane permeability


    1.1.4 Vary pKa
    N
    O

    N
    N
    H

    H2N

    NH

    N
    O

    N
    H

    O
    (I)

    NH2

    N
    O
    PRO3112

    amidine

    Antithrombotic
    but too basic

    Decreased basicity
    N locked into heterocycle

    1.2 Drug stability


    1.2.1 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

    Antirheumatic agent
    D1927

    H
    N

    HS

    CONHMe

    Terminal amide

    N
    H
    O
    C

    H3C
    O

    CH3

    CH3

    Steric
    Shield

    Blocks hydrolysis of terminal amide

    1.2 Drug stability


    1.2.2 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
    O

    O
    C
    H3C

    R
    O

    C
    H2N

    R
    O

    ISOSTERE
    O

    C
    H3C

    R
    O

    CH3

    ISOSTERE

    R
    NH

    1.2 Drug stability


    1.2.2 Electronic shielding of NH2

    O
    R

    N
    H

    N
    H

    C
    R'

    R'

    See carbamoylcholine

    1.2 Drug stability


    1.2.3 Stereoelectronic Effects
    Rationale:
    Steric and electronic effects used in combination
    Increases chemical and metabolic stability
    CH3

    O
    H2N

    C
    O

    N
    H

    CH2CH2NEt2

    C
    CH2NEt2

    PROCAINE

    Local anaesthetic
    (short duration)

    CH3

    LIDOCAINE

    ortho Methyl groups act as steric shields &


    hinder hydrolysis by esterases
    Amide more stable than ester
    (electronic effect)

    See also: oxacillin and bethanechol

    1.2 Drug stability


    1.2.4 Bio-isosteres
    Rationale:
    Replace susceptible group with a different group without affecting
    activity
    Bio-isostere shows improved pharmacokinetic properties
    Bio-isosteres are not necessarily isosteres
    Examples:
    Amides and urethanes for esters (see earlier)
    Du122290 (dopamine antagonist)
    NEt

    NEt
    O

    Pyrrole ring =
    bioisostere for amide

    NH

    NH

    OMe

    OMe
    EtSO2

    EtSO2
    Sultopride

    Du122290

    1.2 Drug stability


    1.2.5 Metabolic blockers
    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
    Me

    Me

    O
    Me
    O

    Me

    Me
    O

    Me

    Me
    H

    Megestrol
    Acetate

    Oral contraceptive
    - limited lifetime

    H
    H

    6
    Me

    Metabolic
    Oxidation

    Me

    H
    H

    Metabolism
    Blocked

    1.2 Drug stability


    1.2.6 Remove / replace susceptible metabolic groups
    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

    Me

    O
    S NH C NH CH2CH2CH2CH3
    O
    O

    Unsusceptible
    group
    Cl

    O
    S NH C NH CH2CH2CH3
    O
    O

    TOLBUTAMIDE

    Metabolism

    HOOC

    O
    S NH C NH CH2CH2CH2CH3
    O
    O

    Rapidly excreted - short lifetime

    Metabolism

    1.2 Drug stability


    1.2.7 Shifting susceptible metabolic groups
    Rationale:

    Used if the metabolically susceptible group is important for binding


    Shift its position to make it unrecognisable to metabolic enzyme
    Must still be recognizable to target

    Example:

    Unsusceptible
    group

    Salbutamol
    Susceptible
    group

    OH

    HO
    OH

    HO

    Shift
    Group

    Me

    CHCH2

    NH

    Me
    Me

    OH

    Me
    NH

    Me
    Me

    Inactive

    CH2

    Me
    NH C

    Catechol
    O-Methyl
    Transferase

    MeO

    CHCH2

    HO

    OH

    Salbutamol

    Catechol
    O-Methyl
    Transferase

    HO

    Me
    Me

    1.2 Drug stability


    1.2.8 Introducing susceptible metabolic groups
    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
    SO2Me

    SO2Me
    Cl
    CH2OH

    Cl
    N

    L787257

    L791456
    N

    CH3

    metabolically
    susceptible

    CO2H

    1.2 Drug stability


    1.2.9 Introducing chemically susceptible groups
    Rationale:
    Used to decrease drug lifetime
    Avoids reliance on metabolic enzymes and individual variations
    Example: Atracurium - i.v. neuromuscular blocking agent
    MeO

    Me
    MeO

    CH2 CH2

    OMe
    OMe

    (CH2)5 O

    OMe

    H
    CH2 CH2

    OMe

    MeO
    OMe

    Stable at acid pH, unstable at blood pH (slightly alkaline)


    Self destructs by Hoffmann elimination and has short lifetime
    Allows anaesthetist to control dose levels accurately
    Quick recovery times after surgery

    1.3 Drug targeting


    1.3.1 Linking a biosynthetic building block
    Rationale:
    Drug smuggled into cell by carrier proteins for natural building block
    (e.g. amino acids or nucleic acid bases)
    Increases selectivity of drugs to target cells and reduces toxicity to
    other cells
    Example:
    Anticancer drugs

    Cl

    Cl
    O

    H3C

    HN
    Cl

    Cl
    O

    Non selective alkylating agent


    Toxic

    H
    N

    Uracil Mustard

    Alkylating group is attached to a nucleic acid base


    Cancer cells grow faster than normal cells and have a greater
    demand for nucleic acid bases
    Drug is concentrated in cancer cells - Trojan horse tactic

    1.3 Drug targeting


    1.3.2 Linking drugs to monoclonal antibodies
    Example:
    Anticancer agents
    Rationale:
    Identify an antigen which is overexpressed on a cancer cell
    Clone a monoclonal antibody for the antigen
    Attach a drug or poison (e.g. ricin) to the monoclonal antibody
    Antibody carries the drug to the cancer cell
    Drug is released at the cancer cell

    1.3 Drug targeting


    1.3.3 Targeting gut infections
    Rationale:
    Design the antibacterial agent to be highly polar or ionized
    Agent will be too polar to cross the gut wall
    Agent will be concentrated at the site of infection
    Example - highly ionized sulfonamides

    1.3 Drug targeting


    1.3.4 Targeting peripheral regions over CNS
    Rationale:
    Increase polarity of the drug

    Drug is less likely to cross the blood brain barrier

    1.4 Reducing drug toxicity


    Rationale:
    Toxicity is often due to specific functional groups
    Remove or replace functional groups known to be toxic e.g.
    aromatic nitro groups
    aromatic amines
    bromoarenes
    hydrazines
    polyhalogenated groups
    hydroxylamines
    Vary substituents
    Vary position of substituents

    1.4 Reducing drug toxicity


    Example - varying substituents

    Fluconazole (Diflucan) - antifungal agent


    N

    N
    N

    N
    OH

    N
    N

    N
    OH

    C
    F

    Cl

    Cl

    UK-47265

    Fluconazole

    Substituents varied
    Less toxic

    Contents
    Part 2: Sections 11.5 11.6
    1.5. Prodrugs
    1.5.1. Prodrugs to improve membrane permeability
    1.5.1.1.
    Esters
    1.5.1.2.
    N-Methylation of amines
    1.5.1.3. Trojan Horse Strategy
    1.5.2. Prodrugs to prolong activity
    1.5.2.1.
    Mask polar groups
    1.5.2.2.
    Add hydrophobic groups

    1.5 Prodrugs
    Definition:
    Inactive compounds which are converted to active compounds in
    the body.
    Uses:
    Improving membrane permeability
    Prolonging activity
    Masking toxicity and side effects
    Varying water solubility
    Drug targeting
    Improving chemical stability

    1.5.1 Prodrugs to improve membrane permeability


    1.5.1.1 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)

    CH3
    RO
    O

    N
    H

    N
    O

    CO2H

    R=Et Enalapril
    R=H Enalaprilit

    1.5.1 Prodrugs to improve membrane permeability


    Example:
    Candoxatril for Candoxatrilat (protease inhibitor)
    OMe

    OMe

    O
    H
    N

    HO
    O

    O
    Candoxatrilat

    O
    CO2H

    O
    Candoxatril

    5-indanyl group

    Varying the ester varies the rate of hydrolysis


    Electron withdrawing groups increase rate of hydrolysis
    (e.g. 5-indanyl)

    H
    N

    Leaving group (5-indanol) is non toxic

    CO2H

    1.5.1 Prodrugs to improve membrane permeability


    1.5.1.2 N-Methylation of amines

    Used to reduce polarity of amines


    Demethylated in liver

    Example:
    Hexobarbitone

    O
    Me
    N

    NH

    O
    Me

    1.5.1 Prodrugs to improve membrane permeability


    1.5.1.3 Trojan Horse Strategy

    Prodrug designed to mimic biosynthetic building block


    Transported across cell membranes by carrier proteins

    Example: Levodopa for dopamine


    HO

    CH2

    HO
    CH2

    HO

    NH2

    Dopamine
    Useful in treating Parkinsons
    Disease
    Too polar to cross cell membranes
    and BBB

    CH2

    HO

    CO2H
    H

    NH2

    Levodopa

    More polar but is an amino acid


    Carried across cell membranes
    by carrier proteins for amino
    acids
    Decarboxylated in cell to
    dopamine

    1.5.1 Prodrugs to improve membrane permeability


    Blood
    supply

    H2N

    Brain
    cells

    H2N

    COOH

    COOH

    Enzyme

    L-Dopa
    H2N

    BLOOD BRAIN
    BARRIER

    Dopamine

    1.5.2 Prodrugs to prolong activity


    1.5.2.1 Mask polar groups

    Reduces rate of excretion

    Example:
    Azathioprine for 6-mercaptopurine

    O2N
    N

    SH
    N

    Me

    6-Mercaptopurine

    Azathioprine

    (suppresses immune response)

    Short lifetime - eliminated too quickly

    Slow conversion to 6-mercaptopurine


    Longer lifetime

    1.5.2 Prodrugs to prolong activity


    Example:
    Valium for nordazepam
    H

    Me

    Cl

    Valium

    N-Demethylation

    Cl

    Nordazepam

    1.5.2 Prodrugs to prolong activity


    1.5.2.2 Add hydrophobic groups

    Drug (and counterion) concentrated in fat tissue


    Slow removal of hydrophobic group
    Slow release into blood supply

    Example:
    Cycloguanil pamoate (antimalarial)

    CO2

    Cl
    NH3
    N

    OH
    CH2

    N
    Me

    OH
    H3N

    Me
    CO2

    Cycloguanil

    Pamoate
    Lipophilic

    1.5.2 Prodrugs to prolong activity


    1.5.2.2 Add hydrophobic groups
    Example:
    Hydrophobic esters of fluphenazine (antipsychotic)
    fatty ester
    N
    N

    (CH2)8CH3

    O
    O

    H
    N

    CF3

    Given by intramuscular injection


    Concentrated in fatty tissue
    Slowly released into the blood supply
    Rapidly hydrolysed in the blood supply

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