Experimental Lipophilicity for Beyond Rule of 5 Compounds
Giuseppe Ermondi, Maura Vallaro, Gilles H. Goetz, Marina Y. Shalaeva, Giulia Caron · Future Drug Discovery · 2019
Aim: To set up a chromatographic strategy for the determination of log P for beyond Rule of 5 (bRo5) drugs. Materials & methods: Capacity factors measured by reverse phase-HPLC. Balance of intermolecular interactions governing systems assessed by partial least squares regression (PLSR) coupled with block relevance anaysis (PLSR-BR) and multiblock PLSR (MBPLSR). Determination of virtual log P obtained through conformational sampling. Results: log k′60 is highly correlated with log P for a dataset of 36 Ro5 compliant compounds (R2 = 0.93, Q2 = 0.90). We refer to the value generated via this method as BRlogP. The balance of intermolecular forces controlling BRlogP and log P are very similar. The ElogPs measured for the bRo5 dataset are significantly higher than corresponding BRlogP. Conclusion: The combination of BRlogP and ElogP provides an experimental lipophilicity range for bRo5 compounds.