Facts, Patterns, and Principles in Drug Discovery: Appraising the Rule of 5 with Measured Physicochemical Data

The rule of 5 was designed to estimate
the likelihood of poor absorption
or permeation, noting the impact of poor solubility. This Perspective
explores the impact of various physicochemical descriptors and contemporary
lipophilicity measurements on permeability and solubility, showing
that the distribution coefficient log D7.4 (rather than log P) is the most impactful
parameter. Molecular weight, almost invariably the defining characteristic
of “beyond the rule of 5” compounds, has little impact
on solubility when log D7.4 measurements
and aromaticity are considered. Predicting permeation is more complex,
given passive and carrier transport mechanisms; however, notable patterns
of behavior are apparent, giving insight even “beyond the rule
of 5”. Recommended best practices should involve using the
facts (measurements) and the patterns they reveal to establish informative
principles rather than fastidious rules.