Discovery of a Gut-Restricted JAK Inhibitor for the Treatment of Inflammatory Bowel Disease
Kristi Leonard, Lisa A. Madge, Paul J. Krawczuk, Aihua Wang, K. D. Kreutter, Genesis M. Bacani, Wenying Chai, Russell C. Smith, Mark S. Tichenor, Michael Harris, Ravi Malaviya, Mark Seierstad, Marguerite E. Johnson, Jennifer D. Venable, Suzie Kim, Gavin C. Hirst, Ashok Mathur, Tadimeti S. Rao, James P. Edwards, Michèle Rizzolio, Tatiana Koudriakova
Abstract
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.