• Mark Zak, Christopher A Hurley, Stuart I Ward, Philippe Bergeron, Kathy Barrett, Mercedesz Balazs, Wade S Blair, Richard Bull, Paroma Chakravarty, Christine Chang, Peter Crackett, Gauri Deshmukh, Jason DeVoss, Peter S Dragovich, Charles Eigenbrot, Charles Ellwood, Simon Gaines, Nico Ghilardi, Paul Gibbons, Stefan Gradl, Peter Gribling, Chris Hamman, Eric Harstad, Peter Hewitt, Adam Johnson, Tony Johnson, Jane R Kenny, Michael F T Koehler, Pawan Bir Kohli, Sharada Labadie, Wyne P Lee, Jiangpeng Liao, Marya Liimatta, Rohan Mendonca, Raman Narukulla, Rebecca Pulk, Austin Reeve, Scott Savage, Steven Shia, Micah Steffek, Savita Ubhayakar, Anne van Abbema, Ignacio Aliagas, Barbara Avitabile-Woo, Yisong Xiao, Jing Yang, and Janusz J Kulagowski.
• Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. mzak@gene.com
• J. Med. Chem. 2013 Jun 13; 56 (11): 4764-85.

AbstractHerein 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.

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