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
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
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DOI：
10.1124/dmd.107.015933
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发表时间：
2007-10-01
影响因子：
3.9
通讯作者：
Christ, David D.
中科院分区：
文献类型：
--
作者：
Qian, Mingxin;Bai, Stephen A.;Christ, David D.
DPC 333 ((2R)-2-((3R)-3-amino-3{4-[ 2-methyl-4-quinolinyl) methoxy] 苯基}-2-oxopyrrolidinyl)-N-羟基-4-methylpentanamide)) 是一种有效的选择性肿瘤坏死因子 (TNF)α 转换酶 (TACE) 抑制剂。它显着抑制啮齿动物、黑猩猩和人类血液中脂多糖诱导的可溶性 TNF-α 产生，IC50 值范围为 17 至 100 nM。在内毒素血症啮齿动物模型中，DPC 333 以剂量依赖性方式抑制 TNF-α 的产生，口服 ED50 范围为 1.1 至 6.1 mg/kg。在大鼠胶原蛋白抗体诱导的关节炎模型中，每天口服 5.5 mg/kg DPC 333 两周，可抑制最大反应约 50%。 DPC 333 广泛分布于包括滑膜在内的组织，滑膜是抗关节炎药物的作用部位。黑猩猩的药代动力学和药效学研究显示，全身清除率为 0.4I/h/kg，V-ss 为 0.6I/kg，口服生物利用度为 17%，抑制 TNF-α 产生的体外 IC50 为 55nM (n = 1)。在男性志愿者单次递增剂量口服 DPC 333 后进行的 I 期临床试验中，终末半衰期为 3 至 6 小时，抑制 TNF-α 产生的离体 IC50 为 113 nM。离体 TNF-α 产生抑制的测量可作为评估 TACE 抑制剂治疗效果的良好生物标志物。总体而言，DPC 333 的药理学特征支持这样的观点：使用 DPC 333 等 TACE 抑制剂抑制 TNF-α 可能通过控制过量的 TNF-α 产生，为治疗包括类风湿性关节炎在内的各种炎症性疾病提供一种新方法。
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.