Novel xanthine oxidase inhibitor for arthritis

新型黄嘌呤氧化酶抑制剂治疗关节炎

• 批准号: 6825387
• 负责人: Zsuzsanna Kinga Zsengeller
• 金额: $ 15.32万
• 依托单位: INOTEK PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6825387
• 关键词: acetylcysteine; allopurinol; antioxidants; antirheumatic agents; arthritis therapy; disease /disorder model; drug screening /evaluation; enzyme activity; inflammation; laboratory mouse; malonaldehyde; myeloperoxidase; nonhuman therapy evaluation; pharmacokinetics; postmortem; rheumatoid arthritis; xanthine oxidase inhibitor

DESCRIPTION (provided by applicant): Xanthine oxidase (XO)-catalyzed generation of superoxide anion is thought to contribute to the pathogenesis of autoimmune arthritis. The relative importance of XO to the pathogenesis of arthritis is demonstrated in numerous rodent models of autoimmune arthritis in which allopurinol, a prototypic XO inhibitor, profoundly reduces joint injury. Accordingly, XO inhibitors have been proposed as a novel class of therapeutics for clinical rheumatoid arthritis (RA). Currently marketed XO inhibitors, allopurinol and oxypurinol, are however considered poor candidates for therapy of clinical RA, as they are weak (IC50 = 40 micromolar) and elicit hypersensitivity reactions in 10% of the population. To address this opportunity, we are developing a series of potent novel XO inhibitors "AN series" (IC50 = 40-200 nM). In a pilot study, we have obtained evidence that enteral administration of a lead AN agent (AN-01-24) reduces the incidence of experimental joint inflammation by 70%. In other regional models of inflammation, our clinical development XO inhibitor, AN-260, has been shown to abolish histologic injury in a DSS model of colitis and to prevent neutrophil infiltration and pro-inflammatory gene expression in an LPS model of ARDS. AN-260 is currently completing formal pre-clinical GLP and GMP studies, in preparation for Phase I clinical testing in 6 months. In order to establish the feasibility of this technology as a potential novel treatment of RA, we now propose to compare the efficacy of AN-260 with the currently marketed XO inhibitor, allopurinol, in two classic rodent models of autoimmune arthritis: a murine model of collagen-induced arthritis and a rat model of adjuvant arthritis. In order to benchmark the efficacy of XO inhibition in these model systems, we will test in parallel the effect of a traditional anti-oxidant, N-acetyl-L-cysteine. We expect that AN-260 will dose-dependently ameliorate gross and histologic injury, preserve joint function, diminish malondialdehyde formation (a marker of lipid peroxidation), and decrease myeloperoxidase activity (a marker of neutrophil infiltration). Based on preliminary data in other inflammatory models, we expect that AN-260 will be more effective than allopurinol and N-acetyl-L-cysteine. In a Phase 2 SBIR, we will carry out a Phase IIa clinical investigation to establish the efficacy of AN-260 in reversing symptomatic clinical RA.

描述（由申请人提供）： 黄嘌呤氧化酶（XO）催化的超氧阴离子的产生被认为有助于自身免疫性关节炎的发病机制。XO对关节炎发病机制的相对重要性在许多自身免疫性关节炎的啮齿动物模型中得到证实，其中别嘌呤醇（原型XO抑制剂）显著降低了关节损伤。因此，XO抑制剂已被提出作为临床类风湿性关节炎（RA）的一类新的治疗药物。然而，目前市售的XO抑制剂别嘌呤醇和羟嘌呤醇被认为是临床RA治疗的不良候选物，因为它们较弱（IC 50 = 40微摩尔），并且在10%的人群中引起超敏反应。为了抓住这个机会，我们正在开发一系列有效的新型XO抑制剂“AN系列”（IC 50 = 40-200 nM）。在一项初步研究中，我们获得的证据表明，肠内给药的铅AN剂（AN-01-24）减少了70%的实验性关节炎症的发病率。在其他局部炎症模型中，我们的临床开发XO抑制剂AN-260已被证明可消除DSS结肠炎模型中的组织学损伤，并可预防LPS ARDS模型中的中性粒细胞浸润和促炎基因表达。AN-260目前正在完成正式的临床前GLP和GMP研究，为6个月内的I期临床试验做准备。为了确定该技术作为RA潜在新型治疗方法的可行性，我们现在建议在两种经典的自身免疫性关节炎啮齿动物模型中比较AN-260与目前市售的XO抑制剂别嘌呤醇的功效：胶原诱导的小鼠模型关节炎和佐剂性关节炎的大鼠模型。为了在这些模型系统中基准XO抑制的功效，我们将平行测试传统抗氧化剂N-乙酰基-L-半胱氨酸的作用。我们预期AN-260将剂量依赖性地改善大体和组织学损伤，保护关节功能，减少丙二醛形成（脂质过氧化的标志物），并降低髓过氧化物酶活性（中性粒细胞浸润的标志物）。基于其他炎症模型的初步数据，我们预计AN-260将比别嘌呤醇和N-乙酰-L-半胱氨酸更有效。在2期SBIR中，我们将进行IIa期临床研究，以确定AN-260逆转症状性临床RA的疗效。