Discovery of a Janus Kinase Inhibitor Bearing a Highly Three-Dimensional Spiro Scaffold: JTE-052 (Delgocitinib) as a New Dermatological Agent to Treat Inflammatory Skin Disorders

Dermatologic disorders such as atopic
dermatitis arise from genetic
and environmental causes and are complex and multifactorial in nature.
Among possible risk factors, aberrant immunological reactions are
one of the leading etiologies. Immunosuppressive agents including
topical steroids are common treatments for these disorders. Despite
their reliability in clinical settings, topical steroids display side
effects, typified by skin thinning. Accordingly, there is a need for
alternate effective and well-tolerated therapies. As part of our efforts
to investigate new immunomodulators, we have developed a series of
JAK inhibitors, which incorporate novel three-dimensional spiro motifs
and unexpectedly possess both excellent physicochemical properties
and antidermatitis efficacy in the animal models. One of these compounds,
JTE-052 (ent-60), also known as delgocitinib,
has been shown to be effective and well-tolerated in human clinical
trials and has recently been approved in Japan for the treatment of
atopic dermatitis as the first drug among Janus kinase inhibitors.