1315497-10-9Relevant 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.
