1384114-32-2Relevant articles and documents
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.
Discovery and optimization of C-2 methyl imidazopyrrolopyridines as potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2
Zak, Mark,Mendonca, Rohan,Balazs, Mercedesz,Barrett, Kathy,Bergeron, Philippe,Blair, Wade S.,Chang, Christine,Deshmukh, Gauri,Devoss, Jason,Dragovich, Peter S.,Eigenbrot, Charles,Ghilardi, Nico,Gibbons, Paul,Gradl, Stefan,Hamman, Chris,Hanan, Emily J.,Harstad, Eric,Hewitt, Peter R.,Hurley, Christopher A.,Jin, Tian,Johnson, Adam,Johnson, Tony,Kenny, Jane R.,Koehler, Michael F. T.,Bir Kohli, Pawan,Kulagowski, Janusz J.,Labadie, Sharada,Liao, Jiangpeng,Liimatta, Marya,Lin, Zhonghua,Lupardus, Patrick J.,Maxey, Robert J.,Murray, Jeremy M.,Pulk, Rebecca,Rodriguez, Madeleine,Savage, Scott,Shia, Steven,Steffek, Micah,Ubhayakar, Savita,Ultsch, Mark,Van Abbema, Anne,Ward, Stuart I.,Xiao, Ling,Xiao, Yisong
, p. 6176 - 6193 (2012/09/07)
Herein we report the discovery of the C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2. The C-2 methyl substituted inhibitor 4 exhibited not only improved JAK1 potency relative to unsubstituted compound 3 but also notable JAK1 vs JAK2 selectivity (20-fold and >33-fold in biochemical and cell-based assays, respectively). Features of the X-ray structures of 4 in complex with both JAK1 and JAK2 are delineated. Efforts to improve the in vitro and in vivo ADME properties of 4 while maintaining JAK1 selectivity are described, culminating in the discovery of a highly optimized and balanced inhibitor (20). Details of the biological characterization of 20 are disclosed including JAK1 vs JAK2 selectivity levels, preclinical in vivo PK profiles, performance in an in vivo JAK1-mediated PK/PD model, and attributes of an X-ray structure in complex with JAK1.
