Discovery of a Gut-Restricted JAK Inhibitor for the Treatment of Inflammatory Bowel Disease

To identify Janus kinase (JAK) inhibitors
that selectively target
gastrointestinal tissues with limited systemic exposures, a class
of imidazopyrrolopyridines with a range of physical properties was
prepared and evaluated. We identified compounds with low intrinsic
permeability and determined a correlation between permeability and
physicochemical properties, clogP and tPSA, for a subset of compounds.
This low intrinsic permeability translated into compounds displaying
high colonic exposure and low systemic exposure after oral dosing
at 25 mg/kg in mouse. In a mouse PK/PD model, oral dosing of lead
compound 2 demonstrated dose-dependent inhibition of
pSTAT phosphorylation in colonic explants post-oral dose but low systemic
exposure and no measurable systemic pharmacodynamic activity. We thus
demonstrate the utility of JAK inhibitors with low intrinsic permeability
as a feasible approach to develop gut-restricted, pharmacologically
active molecules with a potential advantage over systemically available
compounds that are limited by systemic on-target adverse events.