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Relationship between Passive Permeability and Molecular Polarity Using Block Relevance Analysis.

Gilles H Goetz¹, Marina Shalaeva¹, Giulia Caron²

¹Worldwide Medicinal Chemistry, Pfizer Worldwide Research & Development, Pfizer Inc. , Groton, Connecticut 06340, United States.

Molecular Pharmaceutics

|December 31, 2016

Summary

Experimental descriptor of molecular polarity (EPSA) from supercritical fluid chromatography (SFC) correlates with passive permeability in hydrophilic drugs. An EPSA value below 100 enhances the probability of high permeability for Rule of 5 compliant compounds.

Keywords:

EPSA SFC block relevance analysis lipophilicity passive permeability polarity

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Area of Science:

Analytical Chemistry
Computational Chemistry
Pharmacokinetics

Background:

Experimental descriptor of molecular polarity (EPSA) derived from supercritical fluid chromatography (SFC) retention shows correlation with passive permeability.
Previous studies demonstrated EPSA's utility for cyclic peptides.

Purpose of the Study:

To investigate the relationship between EPSA and passive permeability for small molecules.
To interpret the underlying intermolecular forces governing EPSA using block relevance (BR) analysis.

Main Methods:

Application of block relevance (BR) analysis to interpret forces within EPSA.
Determination of EPSA and passive permeability using cell-based assays (RRCK, MDCK-LE, Caco-2) on commercial drugs.
Validation using a large dataset of 1699 Rule of 5 compliant Pfizer compounds.

Main Results:

EPSA is a relevant descriptor for predicting the passive permeability of hydrophilic drugs (CLogP < 1).
For Rule of 5 compliant compounds with CLogP < 1, an EPSA value below 100 significantly increases the likelihood of high passive permeability.

Conclusions:

EPSA serves as a valuable experimental descriptor for molecular polarity and passive permeability.
The findings provide a predictive tool for identifying highly permeable hydrophilic drug candidates.