1440422-20-7Relevant academic research and scientific papers
Discovery of a Gut-Restricted JAK Inhibitor for the Treatment of Inflammatory Bowel Disease
Leonard, Kristi A.,Madge, Lisa A.,Krawczuk, Paul J.,Wang, Aihua,Kreutter, Kevin D.,Bacani, Genesis M.,Chai, Wenying,Smith, Russell C.,Tichenor, Mark S.,Harris, Michael C.,Malaviya, Ravi,Seierstad, Mark,Johnson, Marguerite E.,Venable, Jennifer D.,Kim, Suzie,Hirst, Gavin C.,Mathur, Ashok S.,Rao, Tadimeti S.,Edwards, James P.,Rizzolio, Michele C.,Koudriakova, Tatiana
, p. 2915 - 2929 (2020)
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.
IMIDAZOPYRROLOPYRIDINE AS INHIBITORS OF THE JAK FAMILY OF KINASES
-
, (2018/07/05)
2-((1r,4r)-4-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)cyclohexyl)acetonitrile compounds, pharmaceutical compositions containing them, methods of making them, and methods of using them including methods for treating disease states, disorders, and conditions mediated by JAK, such as inflammatory bowel disease.
Identification of C-2 hydroxyethyl imidazopyrrolopyridines as potent JAK1 inhibitors with favorable physicochemical properties and high selectivity over JAK2
Zak, Mark,Hurley, Christopher A.,Ward, Stuart I.,Bergeron, Philippe,Barrett, Kathy,Balazs, Mercedesz,Blair, Wade S.,Bull, Richard,Chakravarty, Paroma,Chang, Christine,Crackett, Peter,Deshmukh, Gauri,Devoss, Jason,Dragovich, Peter S.,Eigenbrot, Charles,Ellwood, Charles,Gaines, Simon,Ghilardi, Nico,Gibbons, Paul,Gradl, Stefan,Gribling, Peter,Hamman, Chris,Harstad, Eric,Hewitt, Peter,Johnson, Adam,Johnson, Tony,Kenny, Jane R.,Koehler, Michael F. T.,Bir Kohli, Pawan,Labadie, Sharada,Lee, Wyne P.,Liao, Jiangpeng,Liimatta, Marya,Mendonca, Rohan,Narukulla, Raman,Pulk, Rebecca,Reeve, Austin,Savage, Scott,Shia, Steven,Steffek, Micah,Ubhayakar, Savita,Van Abbema, Anne,Aliagas, Ignacio,Avitabile-Woo, Barbara,Xiao, Yisong,Yang, Jing,Kulagowski, Janusz J.
, p. 4764 - 4785 (2013/07/19)
Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.
