Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin

By
use of a structure-based computational method for identification
of structurally novel Janus kinase (JAK) inhibitors predicted to bind
beyond the ATP binding site, a potent series of indazoles was identified
as selective pan-JAK inhibitors with a type 1.5 binding mode. Optimization
of the series for potency and increased duration of action commensurate
with inhaled or topical delivery resulted in potent pan-JAK inhibitor 2 (PF-06263276), which was advanced into clinical studies.