Two Decades under the Influence of the Rule of Five and the Changing Properties of Approved Oral Drugs

Two decades have passed since the
rule of five ushered in the concept
of “drug-like” properties. Attempts to quantify, correlate,
and categorize molecules based on Ro5 parameters evolved into the
introduction of efficiency metrics with far reaching consequences
in decision making by industry leaders and scientists seeking to discover
new medicines. Examination of oral drug parameters approved before
and after the original Ro5 analysis demonstrates that some parameters
such as clogP and HBD remained constant while the cutoffs for parameters
such as molecular weight and HBA have increased substantially over
the past 20 years. The time dependent increase in the molecular weight
of oral drugs during the past 20 years provides compelling evidence
to disprove the hypothesis that molecular weight is a “drug-like”
property. This analysis does not validate parameters that have not
changed as being “drug-like” but instead calls into
question the entire hypothesis that “drug-like” properties
exist.