JAK3covalent inhibitor-2 (compound J1b) is a selective JAK3 inhibitor with oral efficacy, boasting an IC50 value of 7.2 nM. It is characterized by low toxicity, anti-inflammatory properties, and excellent bioavailability.

JAK3:7.2 nM

JAK3 covalent inhibitor-2 demonstrates low cytotoxicity in cell lines HEK293, LO2, chondrocytes, and RAW264.7, with IC50 values (72 h) of 86.82 μM for HEK293, 61.79 μM for LO2, and greater than 32 μM for both chondrocytes and RAW264.7. In metabolic stability studies, the half-life (t1/2) of JAK3 covalent inhibitor-2 (100 mM; 90 min) in human liver microsomes is 13.1 minutes, and 43.9 minutes in rat liver microsomes, with clearance rates of 132.5 mL/min/kg for both species. Additionally, JAK3 covalent inhibitor-2 (0.125-8 μM; 48 h) induces apoptosis in T lymphocytes in a dose-dependent manner.

Anti-inflammatory activity: JAK3 covalent inhibitor-2 (30 mg/kg; p.o.; single dose) reduces the increase in thickness at the site of edema in an ICR mouse model induced by carrageenan. Toxicity test: JAK3 covalent inhibitor-2 (2 g/kg; p.o.; single dose) does not appear to affect the liver and kidneys compared to normal mice, with no observed weight loss or other adverse effects.