Investigation of Janus Kinase (JAK) Inhibitors for Lung Delivery and the Importance of Aldehyde Oxidase Metabolism

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.