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

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 lipopolysaccharideinduced soluble TNF-alpha production in blood from rodents, chimpanzee, and human, with IC50 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 ED50 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 0.4I/ h/ kg, a V-ss of 0.6 I/ kg, an oral bioavailability of 17%, and an ex vivo IC50 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 IC50 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.