title: Novel triazolo-pyrrolopyridines as inhibitors of Janus kinase 1.
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).
authors: Department of Medicinal Chemistry, Argenta, 8/9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom. Chris.Hurley@glpg.com
authors: Christopher A
authors: CA
authors: Hurley
authors: Wade S
authors: WS
authors: Blair
authors: Richard J
authors: RJ
authors: Bull
authors: Christine
authors: C
authors: Chang
authors: Peter H
authors: PH
authors: Crackett
authors: Gauri
authors: G
authors: Deshmukh
authors: Hazel J
authors: HJ
authors: Dyke
authors: Rina
authors: R
authors: Fong
authors: Nico
authors: N
authors: Ghilardi
authors: Paul
authors: P
authors: Gibbons
authors: Peter R
authors: PR
authors: Hewitt
authors: Adam
authors: A
authors: Johnson
authors: Tony
authors: T
authors: Johnson
authors: Jane R
authors: JR
authors: Kenny
authors: Pawan Bir
authors: PB
authors: Kohli
authors: Janusz J
authors: JJ
authors: Kulagowski
authors: Marya
authors: M
authors: Liimatta
authors: Patrick J
authors: PJ
authors: Lupardus
authors: Robert J
authors: RJ
authors: Maxey
authors: Rohan
authors: R
authors: Mendonca
authors: Raman
authors: R
authors: Narukulla
authors: Rebecca
authors: R
authors: Pulk
authors: Savita
authors: S
authors: Ubhayakar
authors: Anne
authors: A
authors: van Abbema
authors: Stuart I
authors: SI
authors: Ward
authors: Bohdan
authors: B
authors: Waszkowycz
authors: Mark
authors: M
authors: Zak
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry; D007700:Kinetics; D008958:Models, Molecular; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D051381:Rats
chemical_list: D011725:Pyridines; D011758:Pyrroles; D053613:Janus Kinase 1; D053614:Janus Kinase 2