title: (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-alpha convertase.
abstract: Tumor necrosis factor-alpha (TNF-alpha), 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-alpha convertase (TACE), an enzyme responsible for proteolytic cleavage of the membrane bound precursor, pro-TNF-alpha. Ro 32-7315 inhibited a recombinant form of TACE (IC(50) = 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-alpha release with IC(50) values of 350 +/- 14 nM (n = 5), 2.4 +/- 0.5 microM (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-alpha 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 placebo-controlled, single-dose study, Ro 32-7315 given orally (450 mg) significantly suppressed ex vivo, LPS-induced TNF-alpha 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.
authors.affiliation: Product Lab, Roche Discovery Welwyn, 40 Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AY, UK.
authors.forename: G
authors.initials: G
authors.lastname: Beck
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authors.initials: G
authors.lastname: Bottomley
authors.forename: D
authors.initials: D
authors.lastname: Bradshaw
authors.forename: M
authors.initials: M
authors.lastname: Brewster
authors.forename: M
authors.initials: M
authors.lastname: Broadhurst
authors.forename: R
authors.initials: R
authors.lastname: Devos
authors.forename: C
authors.initials: C
authors.lastname: Hill
authors.forename: W
authors.initials: W
authors.lastname: Johnson
authors.forename: H-J
authors.initials: HJ
authors.lastname: Kim
authors.forename: S
authors.initials: S
authors.lastname: Kirtland
authors.forename: J
authors.initials: J
authors.lastname: Kneer
authors.forename: N
authors.initials: N
authors.lastname: Lad
authors.forename: R
authors.initials: R
authors.lastname: Mackenzie
authors.forename: R
authors.initials: R
authors.lastname: Martin
authors.forename: J
authors.initials: J
authors.lastname: Nixon
authors.forename: G
authors.initials: G
authors.lastname: Price
authors.forename: A
authors.initials: A
authors.lastname: Rodwell
authors.forename: F
authors.initials: F
authors.lastname: Rose
authors.forename: J-P
authors.initials: JP
authors.lastname: Tang
authors.forename: D S
authors.initials: DS
authors.lastname: Walter
authors.forename: K
authors.initials: K
authors.lastname: Wilson
authors.forename: E
authors.initials: E
authors.lastname: Worth
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000493:pharmacokinetics / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: C459386:2-(1-(hydroxycarbamoyl)-4-phenyl-3-butenyl)-2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide; D016207:Cytokines; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D008070:Lipopolysaccharides; D061965:Matrix Metalloproteinase Inhibitors; D011994:Recombinant Proteins; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606464:Adam17 protein, rat