Linked Life Data

17656469

Source:http://linkedlifedata.com/resource/pubmed/id/17656469

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
10
pubmed:dateCreated
2007-9-25
pubmed:abstractText
DPC 333 ((2R)-2-((3R)-3-amino-3{4-[2-methyl-4-quinolinyl) methoxy] phenyl}-2-oxopyrrolidinyl)-N-hydroxy-4-methylpentanamide)) is a potent and selective inhibitor of tumor necrosis factor (TNF)-alpha-converting enzyme (TACE). It significantly inhibits lipopolysaccharide-induced soluble TNF-alpha production in blood from rodents, chimpanzee, and human, with IC(50) values ranging from 17 to 100 nM. In rodent models of endotoxemia, DPC 333 inhibited the production of TNF-alpha in a dose-dependent manner, with an oral ED(50) ranging from 1.1 to 6.1 mg/kg. Oral dosing of DPC 333 at 5.5 mg/kg daily for 2 weeks in a rat collagen antibody-induced arthritis model suppressed the maximal response by approximately 50%. DPC 333 was distributed widely to tissues including the synovium, the site of action for antiarthritic drugs. Pharmacokinetic and pharmacodynamic studies in chimpanzee revealed a systemic clearance of 0.4 l/h/kg, a V(ss) of 0.6 l/kg, an oral bioavailability of 17%, and an ex vivo IC(50) for the suppression of TNF-alpha production of 55 nM (n = 1). In a phase I clinical trial with male volunteers after single escalating doses of oral DPC 333, the terminal half-life was between 3 and 6 h and the ex vivo IC(50) for suppressing TNF-alpha production was 113 nM. Measurement of the suppression of TNF-alpha production ex vivo may serve as a good biomarker in evaluating the therapeutic efficacy of TACE inhibitors. Overall, the pharmacological profiles of DPC 333 support the notion that suppression of TNF-alpha with TACE inhibitors like DPC 333 may provide a novel approach in the treatment of various inflammatory diseases including rheumatoid arthritis, via control of excessive TNF-alpha production.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0090-9556
pubmed:author
pubmed:issnType
Print
pubmed:volume
35
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1916-25
pubmed:meshHeading
pubmed-meshheading:17656469-ADAM Proteins, pubmed-meshheading:17656469-Adult, pubmed-meshheading:17656469-Animals, pubmed-meshheading:17656469-Anti-Inflammatory Agents, pubmed-meshheading:17656469-Arthritis, Experimental, pubmed-meshheading:17656469-Dogs, pubmed-meshheading:17656469-Double-Blind Method, pubmed-meshheading:17656469-Endotoxemia, pubmed-meshheading:17656469-Female, pubmed-meshheading:17656469-Humans, pubmed-meshheading:17656469-Lipopolysaccharides, pubmed-meshheading:17656469-Male, pubmed-meshheading:17656469-Mice, pubmed-meshheading:17656469-Mice, Inbred BALB C, pubmed-meshheading:17656469-Pan troglodytes, pubmed-meshheading:17656469-Quinolines, pubmed-meshheading:17656469-Rats, pubmed-meshheading:17656469-Rats, Inbred Strains, pubmed-meshheading:17656469-Synovial Fluid, pubmed-meshheading:17656469-Tumor Necrosis Factor-alpha
pubmed:year
2007
pubmed:articleTitle
Pharmacokinetics and pharmacodynamics of DPC 333 ((2R)-2-((3R)-3-amino-3{4-[2-methyl-4-quinolinyl) methoxy] phenyl}-2-oxopyrrolidinyl)-N-hydroxy-4-methylpentanamide)), a potent and selective inhibitor of tumor necrosis factor alpha-converting enzyme in rodents, dogs, chimpanzees, and humans.
pubmed:affiliation
Metabolism and Pharmacokinetics, Bristol-Myers Squibb Company, Princeton, New Jersey, USA. mqian@gene.com
pubmed:publicationType
Journal Article, Randomized Controlled Trial, Clinical Trial, Phase I