Relating Molecular Properties and in Vitro Assay Results to in Vivo Drug Disposition and Toxicity Outcomes

A primary goal of lead optimization is to identify compounds
with improved absorption, distribution, metabolism, excretion, and
toxicity (ADMET) properties. A number of reports have linked computed
molecular properties to desirable in vivo ADMET outcomes, but a significant
limitation of these analyses is the failure to control statistically
for possible covariates. We examine the relationship between molecular
properties and in vitro surrogate assays vs in vivo properties within
173 chemical series from a database of 3773 compounds with rodent
pharmacokinetic and toxicology data. This approach identifies the
following pairs of surrogates as most predictive among those examined:
rat primary hepatocyte (RPH) cytolethality/volume of distribution
(Vd) for in vivo toxicology outcomes,
scaled microsome metabolism/calculated logP for in vivo unbound clearance,
and calculated logD/kinetic aqueous solubility for thermodynamic solubility.
The impact of common functional group substitutions is examined and
provides insights for compound design.