slide1 l.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Physicochemical Properties at Bayer HealthCare (Wuppertal) and Their Use in Medicinal Chemistry PowerPoint Presentation
Download Presentation
Physicochemical Properties at Bayer HealthCare (Wuppertal) and Their Use in Medicinal Chemistry

Loading in 2 Seconds...

play fullscreen
1 / 22

Physicochemical Properties at Bayer HealthCare (Wuppertal) and Their Use in Medicinal Chemistry - PowerPoint PPT Presentation


  • 548 Views
  • Uploaded on

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.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Physicochemical Properties at Bayer HealthCare (Wuppertal) and Their Use in Medicinal Chemistry' - sherlock_clovis


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
slide2

Contents

  • Measured physico-chemical parameters
  • Introduction of our laboratory
  • Model systems for lipophilicity
  • Solubility
  • Use in medicinal chemistry
slide3

Physicochemical Properties Measured

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

slide4

Logistics for HT Physicochemistry

BLJ input for sample identification

Vial collecting rack

Bar-coded vial for sample registration

slide5

cMA,

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

slide6

Our model system

Solid-supported lipid membranes (TRANSIL)

slide7

mlogP vs mlogMA

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

slide8

Why use membrane affinity?

2. comparison with physiological membranes

Influence of cholesterol content has to be considered

slide9

Why use membrane affinity?

Influence of cholesterol

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

slide10

Why use membrane affinity?

Influence of cholesterol

slide11

Why use membrane affinity?

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

Comparison of solubility methods

  • 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

Comparison of solubility methods

  • 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
slide15

O

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

Lessons learned from solubility comparisons

  • 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

Case Histories: The Use of Physicochemical Properties

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

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

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

1.0

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

survival % of HSV infected miceat 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

Conclusion

  • 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