YYSW001

YYSW001 is an orally active and selective JAK1 inhibitor with an IC50 of 6 nM and a Kd of 32.32 μM. It effectively blocks JAK1-dependent STAT6 phosphorylation and IL-6-induced STAT3 phosphorylation. YYSW001 reduces pro-inflammatory cytokine levels, alleviates paw swelling, decreases clinical arthritis scores, mitigates joint damage, and reduces bone loss, making it a valuable compound for rheumatoid arthritis research.

YYSW001 is a potent inhibitor of the JAK1-dependent STAT6 pathway in THP-1 cells, with an IC 50 of 0.041 μM, while it minimally inhibits the JAK2-dependent STAT5 pathway in TF-1 cells (IC 50 = 5.530 μM). It effectively inhibits the proliferation of Ba/F3-TEL-JAK1 cells (IC 50 = 290.2 nM) but shows very low activity against Ba/F3-TEL-JAK2, Ba/F3-TEL-JAK3, and Ba/F3-TEL-TYK2 cells. In human whole blood cells, YYSW001 inhibits IL-6 induced JAK1-dependent STAT3 phosphorylation with IC 50 values of 7065.0 nM in CD3+ T cells and 3001.0 nM in CD14+ monocytes, and it shows a very weak inhibitory effect on GM-CSF induced JAK2-dependent STAT5 phosphorylation. YYSW001 exhibits favorable in vitro ADME properties, including excellent liver microsomal and plasma stability, very low CYP3A4 and hERG inhibitory activity, moderate permeability, and moderate plasma protein binding.

YYSW001 administered via gavage at doses of (3-10 mg/kg; twice daily; for 14 consecutive days) demonstrated dose-dependent therapeutic effects in a collagen-induced arthritis model in rats. In an adjuvant-induced arthritis model in rats, YYSW001 (1-30 mg/kg; twice daily; for 14 days) exhibited a clear dose-dependent anti-arthritic activity. Additionally, YYSW001 (100-200 mg/kg; once daily; for 7 consecutive days) did not show significant safety issues in rats.