Physicochemical Properties at Bayer HealthCare (Wuppertal) and Their Use in Medicinal Chemistry
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Physicochemical Properties at Bayer HealthCare (Wuppertal) and Their Use in Medicinal Chemistry . Contents. Measured physico-chemical parameters Introduction of our laboratory Model systems for lipophilicity Solubility Use in medicinal chemistry. Physicochemical Properties Measured.

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Contents and Their Use in Medicinal Chemistry

  • Measured physico-chemical parameters

  • Introduction of our laboratory

  • Model systems for lipophilicity

  • Solubility

  • Use in medicinal chemistry


Slide3 l.jpg

Physicochemical Properties Measured and Their Use in Medicinal Chemistry

Lipophilicity Membrane Affinity MA

Plasma binding human serum albumin binding HSA

rat serum albumin binding RSA

pKa pKa

Solubility screening in various buffers SOL

equilibrium in buffer

equilibrium in galenic formulations


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Logistics for HT Physicochemistry and Their Use in Medicinal Chemistry

BLJ input for sample identification

Vial collecting rack

Bar-coded vial for sample registration


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cMA, and Their Use in Medicinal Chemistry

cHSA

Solubility

HSA-binding

Membrane affinity

Data Handling by Laboratory Information and Management System (LIMS)

Chemistry

Laboratories

BAYNO/Prepno.,

Barcode, Scale of

Tests, Weight,

Molecular Weight, Principle

investigator, Projekt, Comparison

Lab.-

PDH

PIX

Journal

flag for bases or acids

Sample

Sample-

registration

Reports

PILO-LIMS

Results,

Calibration Data

Rackno.

Rack

Position

Area,

Barcode

Time

Methods

Sequences

Archive

LC/MS/MS

Roboter

LISSY Sample-

Waters

Quattro-Micro

Bar-code scan

preparation

Rack

MTP


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Our model system and Their Use in Medicinal Chemistry

Solid-supported lipid membranes (TRANSIL)


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mlogP vs mlogMA and Their Use in Medicinal Chemistry

6.0

5.0

4.0

logP

3.0

2.0

1.0

0.0

0.0

1.0

2.0

3.0

4.0

5.0

6.0

mlogP (Österberg)

mlogP (Österberg) acid

mlogD7.4 vs mlogMA

mlogP (Österberg) base

4.0

3.0

2.0

1.0

0.0

-4.0

-2.0

0.0

2.0

4.0

6.0

mlogD

-1.0

-2.0

-3.0

-4.0

-5.0

-6.0

logMA

Why Use Membrane Affinity?

1. comparison with other lipophilicity descriptors


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Why use membrane affinity? and Their Use in Medicinal Chemistry

2. comparison with physiological membranes

Influence of cholesterol content has to be considered


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Why use membrane affinity? and Their Use in Medicinal Chemistry

Influence of cholesterol

C. Tradum et al.:Biophysical J. 78 2496-2492


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Why use membrane affinity? and Their Use in Medicinal Chemistry

Influence of cholesterol


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Why use membrane affinity? and Their Use in Medicinal Chemistry

Influence of cholesterol

  • Influence on passive permeation expected to be strong

    • flexibility of plasma membrane is strongly influence by cholesterol, content usually about 80 mol% of phospholipids content

  • Influence on distribution expected to be low

    • 80% of all membranes are intracellular with a cholesterol content about 4 mol% of phospholipids content


  • Slide12 l.jpg

    Comparison of solubility methods and Their Use in Medicinal Chemistry

    • precipitation

      • all compounds

      • small amounts

      • fast analytics

      • compound dissolved in organic solvent

      • oversaturated solutions possible

    • from powder

      • selected compounds

      • large amounts (two samples)

      • specific analytics

      • sensitive to morphology

      • sensitive to purity

      • sensitive to solvent impurities


    Slide13 l.jpg

    Comparison of solubility methods and Their Use in Medicinal Chemistry

    • precipitation

      • Dissolve compound in DMSO (2mg/40µl)

      • Add 10µl of this solution to 1000µl buffer (1% DMSO)

      • Shake for 24h at room temperature

      • Centrifuge to get supernatant

      • Establish LC/MS/MS method

      • Measure calibration standards and probe

    • from powder

      • Weight an appropriate amount of compound as solid

      • Add 1000µl buffer

      • Shake for 24h at room temperature

      • Centrifuge to get supernatant

      • Establish LC/MS/MS method

      • Measure calibration standards and probe


    Slide14 l.jpg

    Comparison of solubility methods and Their Use in Medicinal Chemistry

    EXAMPLES:


    Slide15 l.jpg

    O and Their Use in Medicinal Chemistry

    H

    O

    O

    O

    O

    H

    N

    N

    O

    H

    H

    Cl

    N

    O

    N

    S

    H

    N

    O

    O

    2

    O

    +

    N

    O

    O

    O

    O

    O

    N

    H

    O

    O

    O

    H

    Cl

    O

    H

    N

    H

    N

    N

    H

    O

    O

    S

    O

    O

    O

    H

    O

    O

    N

    O

    Cl

    H

    H

    N

    N

    S

    H

    N

    N

    N

    N

    H

    O

    N

    O

    O

    Cl

    F

    N

    H

    O

    O

    N

    H

    N

    H

    O

    H

    O

    O

    O

    N

    H

    Comparison of solubility methods

    charged

    neutral

    Yalkowsky

    Name

    MOLSTRUCTURE

    compounds

    (water)

    40

    Warfarin

    235

    500

    Primidone

    60

    Metolazone

    88

    6

    Nifedipine

    9

    140

    Ketoprofen

    275

    4

    Glyburide

    1.1

    8.6

    Indomethacin

    240

    11000

    Cimetidine

    800

    Phenacetin

    1080

    14

    Haloperidol

    180

    26

    Phenytoin

    23

    36

    Ibuprofen

    290

    6300

    Acetanilide


    Slide16 l.jpg

    Lessons learned from solubility comparisons and Their Use in Medicinal Chemistry

    • method differences not really critical

    • physical form very important

      differences between research and development result from:

      • morphology differences

      • impurities

      • solvent content

  • counter-ions and buffers are important when compound is charged in solution


  • Slide17 l.jpg

    Case Histories: The Use of Physicochemical Properties and Their Use in Medicinal Chemistry

    Two different projects as examples:

    1. Reducing lipophilicity and HSA binding to increase fraction unbound: erectile disfunction

    2. Influence of solubility on in vivo efficacy: the HSV project


    Slide18 l.jpg

    Reducing Lipophilicity and Protein Binding to Increase Fraction Unbound

    Starting point: initial compound

    moderate effective IC50 PDE-5: 530nM

    DP1 compound: Vardenafil

    highly effective IC50 PDE-5: 2nM

    Insufficient physicochemical properties:

    high membrane affinity: 16500

    high protein binding: 1.7e-5 mol/l

    solubility: below detection limit

    fraction unbound: <1%

    no in vivo efficacy

    improved physicochemical properties:

    reduced membrane affinity: 580

    reduced protein binding: 1.2e-4 mol/l

    solubility: 220 mg/l

    fraction unbound: 14%

    excellent in vivo efficacy


    Slide19 l.jpg

    Reducing lipophilicity and protein binding to increase fraction unbound

    Even the prediction of the in vivo effect from IC50 and fraction unbound (calculated from MA and HSA) was possible

    1.E+02

    initial compound

    1.E+01

    Dose measured in vivo

    1.E+00

    1.E-01

    Vardenafil

    1.E-02

    1.E-02

    1.E-01

    1.E+00

    1.E+01

    1.E+02

    1.E+03

    Dose calculated from IC

    and physicochemical

    50

    properties


    Slide20 l.jpg

    1.0 fraction unbound

    0.9

    0.8

    0.7

    0.6

    0.5

    0.4

    0.3

    0.2

    0.1

    0.0

    0.00

    0.01

    0.10

    1.00

    10.00

    100.00

    Influence of solubility on in vivo efficacy

    Starting point: Example 1

    moderate activity IC50: 750nM

    survival % of HSV infected mice at 60mg/kg vs

    free serum normalized with IC50

    survival % at 60mg/kg

    Physicochemical properties:

    Membrane affinity: 1430

    protein binding: 2e-4 mol/l

    fraction unbound: 10%

    Solubility: 17mg/l

    optimization of physicochemistry not

    necessary, activity has to be improved

    free serum/IC50


    Slide21 l.jpg

    survival % of HSV infected mice fraction unboundat 60mg/kg vs

    free serum normalized with IC50

    1.0

    0.9

    0.8

    0.7

    0.6

    survival % at 60mg/kg

    0.5

    0.4

    0.3

    0.2

    0.1

    0.0

    0.00

    0.01

    0.10

    1.00

    10.00

    100.00

    free serum/IC50

    Influence of solubility on in vivo efficacy

    Example 2: brilliant compound in vitro IC50: <1 nM

    Development candidate

    in vitro activity IC50: 20 nM

    Physicochemical properties:

    Solubility: <0.1 mg/l

    excellent in vivo efficacy when administered as solution, no in vivo efficacy even as micronized powder

    Physicochemical properties:

    Membrane affinity: 1590

    protein binding: 1e-5 mol/l

    fraction unbound: 1%

    Solubility: 2.7mg/l

    good in vivo efficacy


    Slide22 l.jpg

    Conclusion fraction unbound

    • Impact of Physicochemistry Proven

    • Physicochemistry/ADME Implemented in Medicinal Chemistry

    • Properties Routinely Measured for Every Strategic Project

    • Use in Lead Optimization and Exploratory Research Established


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