Vol. 302, Issue 1, 390-396, July 2002

(E)-2(R)-[1(S)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl]-2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide (Ro 32-7315), a Selective and Orally Active Inhibitor of Tumor Necrosis Factor- Convertase

G. Beck, G. Bottomley, D. Bradshaw, M. Brewster, M. Broadhurst, R. Devos, C. Hill, W. Johnson, H.-J. Kim, S. Kirtland, J. Kneer, N. Lad, R. Mackenzie, R. Martin, J. Nixon, G. Price, A. Rodwell, F. Rose, J.-P. Tang, D. S. Walter, K. Wilson and E. Worth

Roche Discovery Welwyn and Pharma Development, Welwyn Garden City, United Kingdom (G. Be., G. Bo., D.B., M. Bre., M. Bro., R.D., C.H., W.J., S.K., N.L., J.N., G.P., A.R., F.R., D.S.W., K.W., E.W.); NCDS, Hoffmann-La Roche Inc., Nutley, New Jersey (H.-J.K., J.-P.T.); PDN, Nippon Roche, Tokyo, Japan (J.K.); and IDU and Pharma Development, Roche Bioscience, Palo Alto (R. Mac., R. Mar.)

Tumor necrosis factor- (TNF-), a cytokine secreted by inflammatory cells, has been implicated in several inflammatory disease states. (E)-2(R)-[1(S)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl]-2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide (Ro 32-7315), 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 (IC₅₀ = 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 IC₅₀ values of 350 ± 14 nM (n = 5), 2.4 ± 0.5 µM (n = 5), and 110 ± 18 nM (n = 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 ED₅₀ 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 placebo-controlled, 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 = 6). These data collectively support the potential use of such a compound for the oral treatment of inflammatory disorders.