NIMBUS Biotechnology

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NIMBUS Biotechnology
Modern Tools for Drug Discovery
www.nimbus-biotechnology.com
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NIMBUS Biotechnology
Modern Tools for Drug Discovery
Innovative tools in ready to go plates
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Bioavailability - an important issue
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Absorption on a cellular level
getting into the blood system
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Distribution
Balance of interactions lipophilicity vs. serum
binding
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Absorption on a cellular level
getting into the blood system
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Passive Transportin search of a good descriptor
Passive Transport In search of a good
descriptor
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Passive Transportin search of a good descriptor
Passive Transport In search of a good
descriptor
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Lipids and Proteins on Solid Supports
Innovative tools in
ready to go plates
Unspecific binding to HSA Prediction of
distribution
Prediction of absorption processes
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TRANSIL

• Determination of LIPOPHILICITY
• Membrane Affinity (logMA)
• Non-covalently attached
• SINGLE LIPID BILAYER
• Different LIPID COMPOSITIONS
• Mimicking natural membranes
• High LONG TERM STABILITY
• 9 months
• DMSO ASSAY CONCENTRATION
• up to 5
• FAST SEPARATION due to the solid support

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Validation log MA (charged and uncharged
compounds) Comparison to liposome
partitioning
Good correlation with liposome approach
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Validation fraction absorbed
0
0
2
4
4
-2
-8
-4
logMA correlates with fraction absorbed
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Validation III
Lot to Lot and Reproducibility
High reproducibility from lot to lot
High reproducibility from measurement to
measurement
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Validation IV
Lab to Lab
Good lab to lab reproducibility
Introduced by Seiffert at NIMBUS Meeting 2005
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TRANSIL?-HSA Properties of the material

• random orientation
• immobilized on a soft and inert surface
• binding sites freely accessible
• stable in presence of organic modifiers (e.g. 5
  DMSO)

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TRANSIL?-HSA Validation TRANSIL-HSA vs.
equilibrium dialysis
good correlation with classical equilibrium
dialysis
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TRANSIL?- HSA Lot-to-lot reproducibility
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TRANSIL?-Assays Principles
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TRANSIL Assays

Available Formats
High-Throughput
High-Precision
Type Compounds per 96-well plate Compounds per 384-well plate
High-Throughput 23 93
High-Precision 10 45
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PK-MapTM
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PK-MapTM ...via Physiology-based ADME
Models
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Validation of the Absorption Model
Compound set (126 marketed drugs)
Human Fabs calculated only from MA and Mw
compared to published in vivo data
Excellent agreement All outliers known as
substrates for active transporters.
Willmann et al., J. Med. Chem. 2004,47, pp
4022-4032
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Validation of the Distribution Model
organ/plasma partition coefficients
Korg/water
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Conclusions
ADME- Optimised Compounds
Lipophilicity/ Membrane Affinity
PK-MAP
logMA
HSA Binding
Log Kd,HSA
Combination of TRANSIL? and PK-MAP as the
most reliable tool for ADME Prediction
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TRANSIL? and TRANSIL?-HSA Benefits and
Summary

• Determination of lipophilicity and serum binding
  in real High Throughput
• Processing time is less than one minute per drug
  in the 384 well format
• First 384 well assay for both parameters
• Small amount of compound needed
• Easy handling Compound addition, separation,
  quantification
• Correlation with established approaches and to
  ADME parameters

High throughput assays for high quality data