Lipophilic Permeability Efficiency Reconciles the Opposing Roles of Lipophilicity in Membrane Permeability and Aqueous Solubility

As drug discovery moves increasingly toward previously “undruggable” targets such as protein–protein interactions, lead compounds are becoming larger and more lipophilic. Although increasing lipophilicity can improve membrane permeability, it can also incur serious liabilities, including poor water solubility, increased toxicity, and faster metabolic clearance. Here we introduce a new efficiency metric, especially relevant to “beyond rule of 5” molecules, that captures, in a simple, unitless value, these opposing effects of lipophilicity on molecular properties. Lipophilic permeability efficiency (LPE) is defined as log D7.4dec/w – mlipocLogP + bscaffold, where log D7.4dec/w is the experimental decadiene–water distribution coefficient (pH 7.4), cLogP is the calculated octanol–water partition coefficient, and mlipo and bscaffold are scaling factors to standardize LPE values across different cLogP metrics and scaffolds. Using a variety of peptidic and nonpeptidic macrocycle drugs, we show that LPE provides ...