Balanced Permeability Index: a multi-parameter index for improved in-vitro permeability

ABSTRACT The optimization of passive permeability is a key objective for orally available small molecule drug candidates. For drugs targeting the central nervous system (CNS), minimizing P-gp mediated efflux is an additional important target for optimization. The physicochemical properties most strongly associated with high passive permeability and lower P-gp efflux are size, polarity and lipophilicity. In this study, a new metric called the Balanced Permeability Index (BPI) was developed that combines these three properties. The BPI was found to be more effective than any single property in classifying molecules based on their permeability and efflux across a diverse range of chemicals and assays. The BPI can also be used to guide optimization in non-traditional small molecule modalities, such as protein degraders, which often lie outside of traditional small molecule space. BPI is easy to understand, allowing researchers to make decisions about which properties to prioritize during the drug development process.