Integrating the Impact of Lipophilicity on Potency and Pharmacokinetic Parameters Enables the Use of Diverse Chemical Space during Small Molecule Drug Optimization

Abstract

Lipophilicity has a dominant effect on many parameters that determine unbound drug exposure as well as drug potency. Despite this, analysis of a large body of drug data indicates lipophilicity has no consistent directional impact on dose. This can be rationalized based on the interplay of the effects of lipophilicity on individual parameter values in pharmacokinetic equations. We believe this undermines the effectiveness of strategies that target specific ranges for drug parameters for which lipophilicity plays such a dominant role. As a result, our research organization no longer leverages the common approach of screening for low intrinsic clearance in vitro to target high unbound exposure in vivo. Instead, we advocate for approaches less biased to lipophilicity through optimization of key parameter ratios controlling dose. We believe this improves efficiency in drug discovery by enabling exploration of broad physicochemical space.

Into the Fray! A Beginner's Guide to Medicinal Chemistry

“…This method is not without its limitations, since alterations to lipophilicity has a downstream impact on the PK properties of a molecule. [125,126] Therefore, increasing hydrophilicity might not always be a suitable method if improving solubility. In these instances, an alternative strategy involves reducing molecular planarity and symmetry, thus disrupting crystal packing, and reducing the energy barrier to dissolution.…”

Multiple linear regression models for predicting the n‑octanol/water partition coefficients in the SAMPL7 blind challenge

“…Thus, log P N has been used for predicting the ability of bioorganic compounds to cross cell membranes [ 3 ]. Nowadays, it is still being used for assessing the impact on pharmacokinetic parameters and potency [ 4 ], metabolism and excretion[ 5 , 6 ], and toxicity [ 7 ] of research compounds.…”

A Retrospective Look at the Impact of Binding Site Environment on the Optimization of TRPA1 Antagonists

“…14 We hypothesize that the cellular assay does not accurately reflect the complex tissue environment where TRPA1 channels reside in vivo and that lower lipophilicity compounds may possess a decreased ability to access the membrane-bound TRPA1 channel within the target tissues. 21 In support of this hypothesis, we noticed that larger in vivo potency shifts correlated with lower measured log D 7.4 . While log D 7.4 is a common measure of bulk hydrophobicity, it does not accurately model interactions with zwitterionic phospholipids (i.e., phospholipophilicity) which may impact target access for TRPA1 antagonists bound at the membrane.…”

“…22 We thought that unbound volume of distribution (V ss,u = V ss /f u ), an in vivo measure of drug distribution in the body, might be a better reflection of the overall tissue (i.e., membrane) binding. 21,23,24 Using rat PK data, we found that molecules with a higher V ss,u possess a reduced potency shift in vivo (see data Table 1). While both log D 7.4 and V ss,u show similar trends, we found V ss,u to be a useful measure of in vivo lipophilicity that helped reconcile PKPD disconnects observed in the program.…”