953039-49-1Relevant articles and documents
Investigation of Janus Kinase (JAK) Inhibitors for Lung Delivery and the Importance of Aldehyde Oxidase Metabolism
Wellaway, Christopher R.,Baldwin, Ian R.,Bamborough, Paul,Barker, Daniel,Bartholomew, Michelle A.,Chung, Chun-Wa,Dümpelfeld, Birgit,Evans, John P.,Fazakerley, Neal J.,Homes, Paul,Keeling, Steven P.,Lewell, Xiao Q.,McNab, Finlay W.,Morley, Joanne,Needham, Deborah,Neu, Margarete,Van Oosterhout, Antoon J. M.,Pal, Anshu,Reinhard, Friedrich B. M.,Rianjongdee, Francesco,Robertson, Craig M.,Rowland, Paul,Shah, Rishi R.,Sherriff, Emma B.,Sloan, Lisa A.,Teague, Simon,Thomas, Daniel A.,Wellaway, Natalie,Wojno-Picon, Justyna,Woolven, James M.,Coe, Diane M.
, p. 633 - 664 (2022/01/03)
The Janus family of tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) play an essential role in the receptor signaling of cytokines that have been implicated in the pathogenesis of severe asthma, and there is emerging interest in the development of small-molecule-inhaled JAK inhibitors as treatments. Here, we describe the optimization of a quinazoline series of JAK inhibitors and the results of mouse lung pharmacokinetic (PK) studies where only low concentrations of parent compound were observed. Subsequent investigations revealed that the low exposure was due to metabolism by aldehyde oxidase (AO), so we sought to identify quinazolines that were not metabolized by AO. We found that specific substituents at the quinazoline 2-position prevented AO metabolism and this was rationalized through computational docking studies in the AO binding site, but they compromised kinome selectivity. Results presented here highlight that AO metabolism is a potential issue in the lung.
QUINAZOLINES FOR PDK1 INHIBITION
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, (2008/06/13)
The invention provides novel quinazoline compounds that are inhibitors of PDK1. Also provided are pharmaceutical compositions including the compounds, and methods of treating proliferative diseases, such as cancers, with the compounds or compositions.
