Implementation of the CYP Index for the Design of Selective Tryptophan-2,3-dioxygenase Inhibitors

A class
of imidazoisoindole (III) heme-binding indoleamine-2,3-dioxygenase
(IDO1) inhibitors were optimized via structure-based drug design into
a series of tryptophan-2,3-dioxygenase (TDO)-selective inhibitors.
Kynurenine pathway modulation was demonstrated in vivo, which enabled evaluation of TDO as a potential cancer immunotherapy
target. As means of mitigating the risk of drug–drug interactions
arising from cytochrome P450 inhibition, a novel property-based drug
design parameter, herein referred to as the CYP Index, was implemented
for the design of inhibitors with appreciable selectivity for TDO
over CYP3A4. We anticipate the CYP Index will be a valuable design
parameter for optimizing CYP inhibition of any small molecule inhibitor
containing a Lewis basic motif capable of binding heme.