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

Abstract

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 D 7.4 dec/w – m lipocLogP + b scaffold, where log D 7.4 dec/w is the experimental decadiene–water distribution coefficient (pH 7.4), cLogP is the calculated octanol–water partition coefficient, and m lipo and b scaffold 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 a functional assessment of the efficiency with which a compound achieves passive membrane permeability at a given lipophilicity.

Discovery of Potent and Selective Halogen-Substituted Imidazole-Thiosemicarbazides for Inhibition of Toxoplasma gondii Growth In Vitro via Structure-Based Design

“…Compounds with a lower log P are more polar and have poorer lipid bilayer permeability while compounds with a higher log P are more lipophilic and thus have better membrane permeability. At the same time, however, serious liabilities for more lipophilic compounds can also be incurred, including poor water solubility, increased toxicity, and faster metabolic clearance [29].…”

Understanding and Improving the Membrane Permeability of VH032-Based PROTACs

“…Here we report a label-free approach for studying the passive permeability of von Hippel–Lindau (VHL)-based PROTAC molecules using the parallel artificial membrane permeability assay (PAMPA) and lipophilic permeability efficiency (LPE). 22 These simple, high-throughput assays correlate strongly with cell-based permeabilities and oral bioavailability while being relatively inexpensive. 23 PAMPA quantifies orders-of-magnitude differences in PROTAC permeabilities with a low limit of quantitation.…”

“…Therefore, we measured lipophilic permeability efficiency (LPE). 22 Originated by our group, LPE quantifies the efficiency with which a compound achieves passive membrane permeability at a given lipophilicity based on the experimental hydrocarbon–water partition coefficient (LogD (dec/w) ) and ALogP. Combining PAMPA and LPE represents a powerful method for assessing how structural features contribute to compound permeability.…”

“…Typically, the addition of a solvent-exposed HBD reduces LPE by 1.8. 22 The tert -Leu-containing 7 has an LPE of 0.4, and its penicillamine counterpart, 15 , has an LPE of −2.3, suggesting that 15 has at least one additional exposed HBD compared to 7 . The same pattern is seen with 8 and 16 that have LPE values of 0.1 and −2.6, respectively.…”

“…For compounds with ALogPs up to ∼4, there is a positive linear correlation between ALogP and permeability. 22 As lipophilicity increases beyond ALogP ∼ 4–5, compounds become insoluble or membrane-retained, and their effective membrane permeabilities diminish ( Figure 6 A). Therefore, designing PROTACs to have an ALogP below 5.0 could bias these compounds toward higher permeabilities.…”