Fraction Lipophilicity Index (FLI)

Abstract

Fraction lipophilicity index (FLI) was developed as a metric for assessing oral drug likeness of ionizable chemical entities, as a weighted combination of log P and log D according to equation: FLI = 2xlog P–log D. The dataset included basic and acidic oral drugs introduced worldwide from 1994-2013. Using MedChemDesigner for logP and logD calculations, a drug-like FLI range of 1-8 is defined, whereas ClogP leads to a broader FLI(C) range of 1-10. A comparison of FLI with Rule of 5 showed that oral drugs with a two fold violation were well accommodated within the specified FLI ranges. Calculations of FLI and FLI(C) for 41 drugs with poor/moderately absorption showed that 40% of them have values outside the suggested drug-like ranges, while a distinct gap in the FLI and FLI(C) space permits the recommendation of ‘safer' ranges: for bases between 5-8 and 5-10 for FLI and FLI(C), respectively, and for acids between 4-7. Application of FLI to a test set of investigational compounds placed all of them within the drug-like FLI/ FLI(C) range, while discriminating two out of three low permeable molecules.