Janus
kinase 1 (JAK1) is a potential target for the treatment of
rheumatoid arthritis (RA). In this study, the introduction of a spiro
ring with a difluoro-substituted cyclopropionamide resulted in the
identification of TUL01101 (compound 36) based on a triazolo[1,5-a]pyridine core of filgotinib. It showed excellent potency
on JAK1 with an IC50 value of 3 nM and exhibited more than
12-fold selectivity for JAK2 and TYK2. Whole blood assay also demonstrated
the high activity and selectivity (37-fold for JAK2). At the same
time, TUL01101 also demonstrated excellent metabolic stability and
pharmacokinetics (PK) profiles were assayed in three species (mouse,
rat, and dog). Moreover, it has been validated for effective activity
in the treatment of RA both in collagen-induced arthritis (CIA) and
adjuvant-induced arthritis (AIA) models, with low dose and low toxicity.
Now, TUL01101 has progressed into phase I clinical trials.
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