Discovery and Optimization of a Novel Series of Highly Selective JAK1 Kinase Inhibitors

Janus
kinases (JAKs) have been demonstrated to be critical in cytokine signaling
and have thus been implicated in both cancer and inflammatory diseases.
The JAK family consists of four highly homologous members: JAK1–3
and TYK2. The development of small-molecule inhibitors that are selective
for a specific family member would represent highly desirable tools
for deconvoluting the intricacies of JAK family biology. Herein, we
report the discovery of a potent JAK1 inhibitor, 24, which displays
∼1000-fold selectivity over the other highly homologous JAK
family members (determined by biochemical assays), while also possessing
good selectivity over other kinases (determined by panel screening).
Moreover, this compound was demonstrated to be orally bioavailable
and possesses acceptable pharmacokinetic parameters. In an in vivo
study, the compound was observed to dose dependently modulate the
phosphorylation of STAT3 (a downstream marker of JAK1 inhibition).