914946-88-6

Once daily oral doses of 5 and 10 mg/kg starting at the time of adjuvant injection on day 1 significantly reduces paw swelling compared with vehicle-treated rats at the end of the study, with the high dose showing nearly complete suppression. The talocrural (ankle) joint space is narrowed. Inflammatory exudates containing neutrophils and cell debris are also evident within the joint space. The joints from animals receiving 10 mg/kg BMS-066 are normal or show minimal changes in both inflammation and bone resorption. Clear reduction of inflammation is also evident in the low dose of BMS-066 (5 mg/kg) and the bone resorption seems to be more focal and less severe compared with the control. Microcomputed tomography of the hind limbs also show that BMS-066 provides a dose-dependent protection against the pitting, loss of bone mass, woven porous bone, and fusion of the small bones evident in the rats. Bone density measurements also show a clear dose-dependent benefit of treatment with BMS-066. Serum drug level measurements in satellite animals on the first day of dosing show that a single dose provides coverage for approximately 3 h (6 h daily with twice daily dosing) of the mouse whole-blood IC₅₀ value against LPS-induced TNF-α. It is also showed that IKKβ inhibitors suppress TNF-α and IL-1β production within these tissues in experimental arthritis model^[1].