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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 -Converting Enzyme in Rodents, Dogs, Chimpanzees, and Humans

Metabolism and Pharmacokinetics (M.Q., S.A.B., B.B., J.-T.W., M.J.F., C.E.G., Y.D., D.D.C.), Biology (R.-Q.L., M.B.C., K.V., R.C.N., J.T.), and Chemistry (T.M., J.J.-W.D., C.P.D.), Bristol-Myers Squibb Company, Princeton, New Jersey

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)--converting enzyme (TACE). It significantly inhibits lipopolysaccharide-induced soluble TNF- 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- 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 0.4 l/h/kg, a V_ss of 0.6 l/kg, an oral bioavailability of 17%, and an ex vivo IC₅₀ for the suppression of TNF- 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- production was 113 nM. Measurement of the suppression of TNF- 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- 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- production.

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