Selective Inhibitors of Human Liver Carboxylesterase Based on a β‑Lapachone Scaffold: Novel Reagents for Reaction Profiling

Carboxylesterases (CEs) are ubiquitous
enzymes that are responsible
for the metabolism of xenobiotics, including drugs such as irinotecan
and oseltamivir. Inhibition of CEs significantly modulates the efficacy
of such agents. We report here that β-lapachone is a potent,
reversible CE inhibitor with Ki values
in the nanomolar range. A series of amino and phenoxy analogues have
been synthesized, and although the former are very poor inhibitors,
the latter compounds are highly effective in modulating CE activity.
Our data demonstrate that tautomerism of the amino derivatives to
the imino forms likely accounts for their loss in biological activity.
A series of N-methylated amino derivatives, which are unable to undergo
such tautomerism, were equal in potency to the phenoxy analogues and
demonstrated selectivity for the liver enzyme hCE1. These specific
inhibitors, which are active in cell culture models, will be exceptionally
useful reagents for reaction profiling of esterified drugs in complex
biological samples.