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

Abstract

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.