The Janus kinases (JAK1, JAK2, JAK3 and TYK2) are a family of intracellular tyrosine kinases that play an essential role in the signalling of numerous cytokines that have been implicated in the pathogenesis of inflammatory diseases. There is emerging interest in the development of small-molecule inhaled JAK inhibitors for severe asthma, as this approach targets multiple disease pathways to achieve broader efficacy compared to single cytokine approaches. Accordingly, this presentation describes the identification of a quinazoline lead series, and the optimisation of JAK potency, solubility and lung retention, aided by structure-based design. Two exemplars from the series were evaluated in an <i>in vivo</i> mouse model following intranasal administration to assess their ability to be retained in the lung, but only low lung concentrations of parent compound were measured which, after further investigation, was primarily due to metabolism by aldehyde oxidase (AO). Although AO is predominately expressed in liver and other tissues, the lower levels expressed in lung were significant enough to limit lung exposure. This, combined with the well-documented risk of advancing an AO substrate into the clinic, led us to identify compounds which were not metabolised by AO. We achieved this by incorporating specific substituents at the quinazoline 2-position and rationalised the lack of AO metabolism through computational docking studies in the AO binding site.

Design and synthesis of Janus kinase inhibitors for inhaled delivery and the importance of aldehyde oxidase metabolism in the lung

2019 Fall National Meeting

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