spacer The Jak1 kinase domain in complex with inhibitor
Primary citation
Title Novel triazolo-pyrrolopyridines as inhibitors of Janus kinase 1.
Authors Hurley, C.A.search; Blair, W.S.search; Bull, R.J.search; Chang, C.search; Crackett, P.H.search; Deshmukh, G.search; Dyke, H.J.search; Fong, R.search; Ghilardi, N.search; Gibbons, P.search; Hewitt, P.R.search; Johnson, A.search; Johnson, T.search; Kenny, J.R.search; Kohli, P.B.search; Kulagowski, J.J.search; Liimatta, M.search; Lupardus, P.J.search; Maxey, R.J.search; Mendonca, R.search; Narukulla, R.search; Pulk, R.search; Ubhayakar, S.search; van Abbema, A.search; Ward, S.I.search; Waszkowycz, B.search; Zak, M.search
Journal BIOORG.MED.CHEM.LETT.search vol:23, pag:3592-3598 (2013), Identifiers: PubMed ID (23642482)search DOI (10.1016/j.bmcl.2013.04.018)
Abstract The 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).
MeSH terms
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