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.