Tumor necrosis factor-␣ (TNF-␣), a cytokine secreted by inflammatory cells, has been implicated in several inflammatory disease, is a potent, orally active inhibitor of the TNF-␣ convertase (TACE), an enzyme responsible for proteolytic cleavage of the membrane bound precursor, pro-TNF-␣. Ro 32-7315 inhibited a recombinant form of TACE (IC 50 ϭ 5.2 nM) with selectivity over related matrix metalloproteinases. In a cellular assay system, THP-1 cell line, and in human and rat whole blood, Ro 32-7315 significantly reduced lipopolysaccharide (LPS)-induced TNF-␣ release with IC 50 values of 350 Ϯ 14 nM (n ϭ 5), 2.4 Ϯ 0.5 M (n ϭ 5), and 110 Ϯ 18 nM (n ϭ 5), respectively. Oral administration of Ro 32-7315 to Wistar rats caused a dose-dependent inhibition of LPS-induced release of systemic TNF-␣ with an ED 50 of 25 mg/kg. Treatment (days 0 -14) of Allen and Hamburys hooded rats with Ro 32-7315 (2.5, 5, 10, and 20 mg/kg, i.p., twice daily) significantly reduced adjuvant-induced secondary paw swelling (42, 71, 83, and 93%, respectively) as compared with the vehicle group. In the Ro 32-7315-treated group, the reduced paw swelling was associated with improved lesion score and joint mobility. Furthermore, in a placebocontrolled, single-dose study, Ro 32-7315 given orally (450 mg) significantly suppressed ex vivo, LPS-induced TNF-␣ release in the whole-blood samples taken from healthy male and female volunteers (mean inhibition of 42% over a 4-h duration, n ϭ 6). These data collectively support the potential use of such a compound for the oral treatment of inflammatory disorders.
