• Bioorg. Med. Chem. Lett. · Dec 2012

    Structure-based discovery of C-2 substituted imidazo-pyrrolopyridine JAK1 inhibitors with improved selectivity over JAK2.

    • Sharada Labadie, Peter S Dragovich, Kathy Barrett, Wade S Blair, Philippe Bergeron, Christine Chang, Gauri Deshmukh, Charles Eigenbrot, Nico Ghilardi, Paul Gibbons, Christopher A Hurley, Adam Johnson, Jane R Kenny, KohliPawan BirPB, Janusz J Kulagowski, Marya Liimatta, Patrick J Lupardus, Rohan Mendonca, Jeremy M Murray, Rebecca Pulk, Steven Shia, Micah Steffek, Savita Ubhayakar, Mark Ultsch, Anne van Abbema, Stuart Ward, and Mark Zak.
    • Small Molecule Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States. sharadal@gene.com
    • Bioorg. Med. Chem. Lett. 2012 Dec 15; 22 (24): 7627-33.

    AbstractHerein we describe our successful efforts in obtaining C-2 substituted imidazo-pyrrolopyridines with improved JAK1 selectivity relative to JAK2 by targeting an amino acid residue that differs between the two isoforms (JAK1: E966; JAK2: D939). Efforts to improve cellular potency by reducing the polarity of the inhibitors are also detailed. The X-ray crystal structure of a representative inhibitor in complex with the JAK1 enzyme is also disclosed.Copyright © 2012 Elsevier Ltd. All rights reserved.

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