Identification of C-2 hydroxyethyl imidazopyrrolopyridines as potent JAK1 inhibitors with favorable physicochemical properties and high selectivity over JAK2

…, SI Ward, P Bergeron, K Barrett, M Balazs…

Index: 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. Journal of Medicinal Chemistry, 2013 , vol. 56, # 11 p. 4764 - 4785

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Citation Number: 21

Abstract

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 ...