RT Journal Article
SR Electronic
T1 (<em>E</em>)-2(<em>R</em>)-[1(<em>S</em>)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-2′-(methanesulfonyl)-4-methylvalerohydrazide  (Ro 32-7315), a Selective and Orally Active Inhibitor of Tumor Necrosis Factor-α Convertase
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 390
OP 396
DO 10.1124/jpet.302.1.390
VO 302
IS 1
A1 G. Beck
A1 G. Bottomley
A1 D. Bradshaw
A1 M. Brewster
A1 M. Broadhurst
A1 R. Devos
A1 C. Hill
A1 W. Johnson
A1 H.-J. Kim
A1 S. Kirtland
A1 J. Kneer
A1 N. Lad
A1 R. Mackenzie
A1 R. Martin
A1 J. Nixon
A1 G. Price
A1 A. Rodwell
A1 F. Rose
A1 J.-P. Tang
A1 D. S. Walter
A1 K. Wilson
A1 E. Worth
YR 2002
UL http://jpet.aspetjournals.org/content/302/1/390.abstract
AB Tumor necrosis factor-α (TNF-α), 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-α convertase (TACE), an enzyme responsible for proteolytic cleavage of the membrane bound precursor, pro-TNF-α. 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-α 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-α 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-α 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. The American Society for Pharmacology and Experimental Therapeutics