Discovery of YYSW001: A Highly Selective, Orally Bioavailable JAK1 Inhibitor Achieving Efficacy under a Moderate-Inhibition Strategy with Improved Preclinical Tolerability

Janus
kinase 1 (JAK1)-preferential inhibition has emerged
as a
promising approach to maintain anti-inflammatory efficacy while minimizing
hematopoietic adverse effects attributed to JAK2 blockade. Guided
by a design concept aiming for sufficient JAK1 target engagement without
excessive pathway suppression, we designed and optimized a series
of imidazopyrrolopyridines to identify compound 40 (YYSW001). YYSW001 exhibited potent JAK1 inhibition
(IC50 = 6 nM) with >50-fold selectivity over JAK2 and
strong
cellular activity. Pharmacokinetic evaluation revealed 61.8% oral
bioavailability. In rat collagen-induced arthritis (CIA) and adjuvant-induced
arthritis (AIA) models, YYSW001 demonstrated therapeutic
efficacy comparable to upadacitinib. Consistent with its JAK1/JAK2
selectivity, YYSW001 reduced JAK2-associated liabilities,
including hematologic dysfunction and weight loss, relative to upadacitinib.
Overall, YYSW001 represents a preferential JAK1 inhibitor
with a favorable efficacy-tolerability profile, which is currently
undergoing preclinical development.