• Bioorg. Med. Chem. Lett. · Jun 2013

    Letter

    Novel triazolo-pyrrolopyridines as inhibitors of Janus kinase 1.

    • Christopher A Hurley, Wade S Blair, Richard J Bull, Christine Chang, Peter H Crackett, Gauri Deshmukh, Hazel J Dyke, Rina Fong, Nico Ghilardi, Paul Gibbons, Peter R Hewitt, Adam Johnson, Tony Johnson, Jane R Kenny, KohliPawan BirPB, Janusz J Kulagowski, Marya Liimatta, Patrick J Lupardus, Robert J Maxey, Rohan Mendonca, Raman Narukulla, Rebecca Pulk, Savita Ubhayakar, Anne van Abbema, Stuart I Ward, Bohdan Waszkowycz, and Mark Zak.
    • Department of Medicinal Chemistry, Argenta, 8/9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom. Chris.Hurley@glpg.com
    • Bioorg. Med. Chem. Lett. 2013 Jun 15; 23 (12): 3592-8.

    AbstractThe identification of a novel fused triazolo-pyrrolopyridine scaffold, optimized derivatives of which display nanomolar inhibition of Janus kinase 1, is described. Prototypical example 3 demonstrated lower cell potency shift, better permeability in cells and higher oral exposure in rat than the corresponding, previously reported, imidazo-pyrrolopyridine analogue 2. Examples 6, 7 and 18 were subsequently identified from an optimization campaign and demonstrated modest selectivity over JAK2, moderate to good oral bioavailability in rat with overall pharmacokinetic profiles comparable to that reported for an approved pan-JAK inhibitor (tofacitinib).Copyright © 2013 Elsevier Ltd. All rights reserved.

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