The JAK/STAT signaling pathway is a key regulator of immunity/inflammation, blood cell production, and cell proliferation. The JAKs (Janus Kinases) play a central role in this pathway, becoming phosphorylated and activated upon cytokines binding to their receptors. Of the four known JAKs (JAK1, JAK2, JAK3, and TYK2), JAK1 is known to be especially important for signaling of asthma relevant cytokines such as IL-13 and IL-4. There is, thus, interest in targeting JAK1 inhibition as a potential treatment for asthma. Although multiple JAK inhibitors have either been approved as drugs or are in late stage clinical development, all such compounds are orally delivered systemic agents for diseases such as rheumatoid arthritis or polycythemia vera. The side effect profiles of these orally delivered compounds are likely not compatible with the asthma population. However, localizing JAK inhibition to the lung may provide therapeutic benefit in asthma while providing an improved systemic safety margin. This disclosure will describe the discovery of inhaled JAK1 inhibitors intended for local action in the lung. Optimization of potency, selectivity, and lung retention will be presented. Finally, the preclinical characterization of an optimized molecule, including efficacy in an ovalbumin-induced model of eosinophilic asthma will disclosed.<br/>

Inhaled Janus kinase 1 (JAK1) inhibitors as potential treatments for asthma

255th National Meeting (2018)

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