Identification of 2‑Imidazopyridine and 2‑Aminopyridone Purinones as Potent Pan-Janus Kinase (JAK) Inhibitors for the Inhaled Treatment of Respiratory Diseases

Janus kinases (JAKs)
have a key role in regulating the expression
and function of relevant inflammatory cytokines involved in asthma
and chronic obstructive pulmonary disease. Herein are described the
design, synthesis, and pharmacological evaluation of a series of novel
purinone JAK inhibitors with profiles suitable for inhaled administration.
Replacement of the imidazopyridine hinge binding motif present in
the initial compounds of this series with a pyridone ring resulted
in the mitigation of cell cytotoxicity. Further systematic structure–activity
relationship (SAR) efforts driven by structural biology studies led
to the discovery of pyridone 34, a potent pan-JAK inhibitor
with good selectivity, long lung retention time, low oral bioavailability,
and proven efficacy in the lipopolysaccharide-induced rat model of
airway inflammation by the inhaled route.