An update on lipophilic efficiency as an important metric in drug design.

Introduction: Lipophilic efficiency (LipE) and lipophilic metabolic efficiency (LipMetE) are valuable tools that can be utilized as part of a multiparameter optimization process to advance a hit to a clinical quality compound.

Areas covered: This review covers recent, effective use cases of LipE and LipMetE that have been published in the literature over the past 5 years. These use cases resulted in the delivery of high-quality molecules that were brought forward to in vivo work and/or to clinical studies. The authors discuss best-practices for using LipE and LipMetE analysis, combined with lipophilicity-focused compound design strategies, to increase the speed and effectiveness of the hit to clinical quality compound optimization process.

Expert opinion: It has become well established that increasing LipE and LipMetE within a series of analogs facilitates the improvement of broad selectivity, clearance, solubility, and permeability and, through this optimization, also facilitates the achievement of desired pharmacokinetic properties, efficacy, and tolerability. Within this article, we discuss lipophilic efficiency-focused optimization as a tool to yield high-quality potential clinical candidates. It is suggested that LipE/LipMetE-focused optimization can facilitate and accelerate the drug-discovery process.