PMID- 12065742
OWN - NLM
STAT- MEDLINE
DCOM- 20020712
LR  - 20190607
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 302
IP  - 1
DP  - 2002 Jul
TI  - (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.
PG  - 390-6
AB  - 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.
FAU - Beck, G
AU  - Beck G
AD  - Product Lab, Roche Discovery Welwyn, 40 Broadwater Road, Welwyn Garden City, 
      Hertfordshire AL7 3AY, UK.
FAU - Bottomley, G
AU  - Bottomley G
FAU - Bradshaw, D
AU  - Bradshaw D
FAU - Brewster, M
AU  - Brewster M
FAU - Broadhurst, M
AU  - Broadhurst M
FAU - Devos, R
AU  - Devos R
FAU - Hill, C
AU  - Hill C
FAU - Johnson, W
AU  - Johnson W
FAU - Kim, H-J
AU  - Kim HJ
FAU - Kirtland, S
AU  - Kirtland S
FAU - Kneer, J
AU  - Kneer J
FAU - Lad, N
AU  - Lad N
FAU - Mackenzie, R
AU  - Mackenzie R
FAU - Martin, R
AU  - Martin R
FAU - Nixon, J
AU  - Nixon J
FAU - Price, G
AU  - Price G
FAU - Rodwell, A
AU  - Rodwell A
FAU - Rose, F
AU  - Rose F
FAU - Tang, J-P
AU  - Tang JP
FAU - Walter, D S
AU  - Walter DS
FAU - Wilson, K
AU  - Wilson K
FAU - Worth, E
AU  - Worth E
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 
      (2-(1-(hydroxycarbamoyl)-4-phenyl-3-butenyl)-2'-isobutyl-2'-(methanesulfonyl)-4-methylvalerohydrazide)
RN  - 0 (Cytokines)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Hydroxamic Acids)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Matrix Metalloproteinase Inhibitors)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Sulfonamides)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 3.4.24.- (ADAM Proteins)
RN  - EC 3.4.24.- (Metalloendopeptidases)
RN  - EC 3.4.24.86 (ADAM17 Protein)
RN  - EC 3.4.24.86 (ADAM17 protein, human)
RN  - EC 3.4.24.86 (Adam17 protein, rat)
SB  - IM
MH  - ADAM Proteins
MH  - ADAM17 Protein
MH  - Animals
MH  - Arthritis, Experimental/drug therapy
MH  - Cell Line
MH  - Cytokines/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Inhibitors/pharmacokinetics/*pharmacology
MH  - Female
MH  - Humans
MH  - Hydroxamic Acids/pharmacokinetics/*pharmacology
MH  - Lipopolysaccharides/pharmacology
MH  - Male
MH  - Matrix Metalloproteinase Inhibitors
MH  - Metalloendopeptidases/*antagonists & inhibitors
MH  - Rats
MH  - Rats, Wistar
MH  - Recombinant Proteins/metabolism
MH  - Sulfonamides/pharmacokinetics/*pharmacology
MH  - Tumor Necrosis Factor-alpha/*metabolism
EDAT- 2002/06/18 10:00
MHDA- 2002/07/13 10:01
CRDT- 2002/06/18 10:00
PHST- 2002/06/18 10:00 [pubmed]
PHST- 2002/07/13 10:01 [medline]
PHST- 2002/06/18 10:00 [entrez]
AID - 10.1124/jpet.302.1.390 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2002 Jul;302(1):390-6. doi: 10.1124/jpet.302.1.390.