Novel triazolo-pyrrolopyridines as inhibitors of Janus kinase 1

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 corr...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2013-06, Vol.23 (12), p.3592-3598
Main Authors: Hurley, Christopher A., Blair, Wade S., Bull, Richard J., Chang, Christine, Crackett, Peter H., Deshmukh, Gauri, Dyke, Hazel J., Fong, Rina, Ghilardi, Nico, Gibbons, Paul, Hewitt, Peter R., Johnson, Adam, Johnson, Tony, Kenny, Jane R., Kohli, Pawan Bir, Kulagowski, Janusz J., Liimatta, Marya, Lupardus, Patrick J., Maxey, Robert J., Mendonca, Rohan, Narukulla, Raman, Pulk, Rebecca, Ubhayakar, Savita, van Abbema, Anne, Ward, Stuart I., Waszkowycz, Bohdan, Zak, Mark
Format: Article
Language:English
Subjects:
Animals
bioavailability
chemistry
Crystallography, X-Ray
JAK1
JAK1 inhibitor
JAK2
Janus kinase
Janus Kinase 1 - antagonists & inhibitors
Janus Kinase 1 - chemistry
Janus Kinase 2 - antagonists & inhibitors
Janus Kinase 2 - chemistry
Kinetics
Models, Molecular
non-specific protein-tyrosine kinase
oral exposure
permeability
pharmacokinetics
Pyridines - chemistry
Pyridines - pharmacology
Pyrroles - chemistry
Pyrroles - pharmacology
Rats
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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).
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2013.04.018