Better (Combinatorial) Screening through PhysChem
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Transcript of Better (Combinatorial) Screening through PhysChem
Better Better (Combinatorial) (Combinatorial)
ScreeningScreeningthroughthrough
PhysChemPhysChem
Robert S DeWitte, PhDAdvanced 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
Stomach
1.4-2.1
3 - 7
Ileum
6.8 - 8.0
6.8 - 8.0
Colon
5 - 8
5 - 8pH
physiology & biophysics of GI tract
fasted state
fed state
Jejunum
4.4 - 6.6
5.2 - 6.2
0.1 m2
0.3 m2
Dressman, Amidon, Reppas, Shah, Pharm. Res. 1998, 15, 11.
0.5-3.5 hr 3-4 hr
1 - 3 d
120 m2
acids
bases
Lipophilicity is pH dependent
LogP is not Enough!
Solubility is pH dependent
Only ACD predicts solubility
as a function of pH!
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