Discovery of Clinical Candidate (1<i>R</i>,4<i>r</i>)-4-((<i>R</i>)-2-((<i>S</i>)-6-Fluoro-5<i>H</i>-imidazo[5,1-<i>a</i>]isoindol-5-yl)-1-hydroxyethyl)cyclohexan-1-ol (Navoximod), a Potent and Selective Inhibitor of Indoleamine 2,3-Dioxygenase 1

Abstract

A novel class of 5-substituted 5<i>H</i>-imidazo[5,1-<i>a</i>]isoindoles are described as potent inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1). A structure-based drug design approach was used to elaborate the 5<i>H</i>-imidazo[5,1-<i>a</i>]isoindole core and to improve potency and pharmacological properties. Suitably placed hydrophobic and polar functional groups in the lead molecule allowed improvement of IDO1 inhibitory activity while minimizing off-target liabilities. Structure-activity relationship studies focused on optimizing IDO1 inhibition potency and a pharmacokinetic profile amenable to oral dosing while controlling CYP450 and hERG inhibitory properties.