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