Transcript LogD - University of Sheffield

Better
(Combinatorial)
Screening
through
PhysChem
Robert S DeWitte, PhD
Advanced Chemistry Development Inc.
Toronto Ontario Canada
Advanced Chemistry Development
Why do Physical Properties
create opportunity?
 Absorption and Activity are two central
themes in Drug Discovery Research
– Absorption relates the ability of a potential drug to
enter the blood stream after administration
• Driven by solubility and lipophilicity
– Activity relates the ability of a potential drug to
elicit the desired effect once it reaches the site of
action
• Driven by hydrogen bonds and hydrophobic
effect
– These often come one at the expense of the other,
so simultaneously optimizing both is difficult
 Experimental Design
Absorption
 Poor Physical Properties account for more
than half of the failures of drug candidates
– Over 50% of Drug Candidates are rejected due to
poor pharmacokinetic properties
– Almost 30% of failures occur during development
– Too Late for Chemistry
 Formulation
– An expensive option
– Not always able to rescue a difficult agent
Absorption
 Many compounds of biological interest are
not neutral
– Hydrophobicity (LogD) is pH dependent
– Solubility is pH dependent
 Presentation from Pfizer this week at AAPS
–
–
–
–
Absorption = Solubility X Permeability
Permeability varies 40 fold
Solubility varies 1,000,000 fold
Therefore solubility is key
physiology &
biophysics of
GI tract
120 m2
0.3 m2
3-4 hr
0.5-3.5 hr
bases
0.1 m2
1-3d
acids
pH
Stomach
Jejunum
Ileum
Colon
1.4-2.1
4.4 - 6.6
6.8 - 8.0
5-8
fasted state
3-7
5.2 - 6.2
6.8 - 8.0
5-8
fed state
Dressman, Amidon, Reppas, Shah, Pharm. Res. 1998, 15, 11.
Lipophilicity is pH dependent
Solubility is pH dependent
Experimental Design
 Combinatorial Libraries
– Early Combinatorial Chemistry was aimed at large
mix-and-split libraries
– Most compounds were too greasy for screening
– Recently, targeted parallel synthesis has become
popular
– Smaller focused libraries provide the opportunity for
more careful screening
 Opportunities for better screening
– Compound Pooling
– Library Design
– Screening Conditions
Opportunities for better
screening
 Compound Pooling
– Compounds can be grouped according to their
properties
– Like with like for similar physical sample
characteristics
• pKa’s of ionizable centres to present
samples as neutral forms
• Solubility to select a suitable target
concentration
– Maximally Diverse for easier hit identification
• Molecular Weight (MS)
• LogD (HPLC)
Opportunities for better
screening
 Library Design
– The Space of Physical Properties can be
sampled with maximal diversity
– Broadest possible range of LogD, pKa values
to generate the most information
– Targeted ranges
– Keep Solubility in range, vary LogD
systematically, keep pKa near 9.6
– Size compensation
– Vary the size of substituents without
affecting LogD
Opportunities for better
screening
 Screening Conditions
– If compound pooling has been done, you can
• Vary pH to systematically affect LogD
• Vary pH to assure that the neutral form (or
+ve ion form) is presented to the target
• Vary the dilution of the target to
compensate for solubility effects
– Even without compound pooling, reference to
the distribution of Physical Properties in the
library will inform the conditions or
interpretation of results
Modes of Application
 Virtual Screening
– At design time
 ADME Screening
– Pool compounds to simplify setting experimental
conditions
• e.g: for optimal HPLC retention times
 HTS Screening
– Pool compounds to systematize the variation among
observations, quenching significant noise, providing
enhanced signal-to-noise ratio
User Training and Libraries
 At the time that combinatorial library is being
planned
– Typically, at least one related lead compound is
known
– Select minimalist related lead compound for
experimental measurement
– Use measurement for user training
– Enumerate combi-library
– Predict Physical properties
– Prune Library
– Pool Compounds
– Establish Screening Conditions
User Training System
Summary
 Physical properties provide insight into
absorption, activity and experimental design
 Trends that reduce the size of combinatorial
libraries provide the opportunity to reduce
noise in screening by using ACD/PhysChem to
– Pool compounds
– Design libraries
– Select screening conditions
 User training in conjunction with PhysChem
Batch provides an accurate route to Physical
Property Prediction for Combi-chem
applications