baricitinib and Arthritis

The Janus kinase (JAK) family of tyrosine kinases has been proven to provide targeted immune modulation. Orally available JAK inhibitors have been used for the treatment of immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA). Here, we report the design, synthesis and biological evaluation of 4-(4,5,6,7-tetrahydrofuro[3,2-c]pyridin-2-yl) pyrimidin-2-amino derivatives as JAK inhibitors. Systematic structure-activity relationship studies led to the discovery of compound 7j, which strongly inhibited the four isoforms of JAK kinases. Molecular modeling rationalized the importance of cyanoacetyl and phenylmorpholine moieties. The in vivo investigation indicated that compound 7j possessed favorable pharmacokinetic properties and displayed slightly better anti-inflammatory efficacy than tofacitinib at the same dosage. Accordingly, compound 7j was advanced into preclinical development.

Topics: Administration, Oral; Amines; Animals; Anti-Inflammatory Agents; Arthritis; Binding Sites; Disease Models, Animal; Drug Evaluation, Preclinical; Half-Life; Humans; Janus Kinase Inhibitors; Janus Kinases; Molecular Docking Simulation; Protein Isoforms; Pyrimidines; Rats; Structure-Activity Relationship