101421-33-4Relevant 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.
ISOQUINOLINE DERIVATIVES AS SIK2 INHIBITORS
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Paragraph 00137; 00320, (2021/05/07)
Provided are compounds of the Formula I, and salts and solvates thereof: (I) wherein R1, R2, R3, X1, X2, X3 and Z are defined in the specification. The compounds are inhibitors of salt-inducible kinase (SIK), particular SIK2, and are useful in therapy, particularly in the treatment of a proliferative disorder, a benign neoplasm, pathological angiogenesis, an inflammatory disease or condition, a musculoskeletal disease or condition, an autoimmune disease, a haematological disease or condition, a neurological disease or condition, a psychiatric disorder, or a metabolic disorder.
