Peroxynitrite decomposition catalyst for bowel disease

肠道疾病的过氧亚硝酸盐分解催化剂

• 批准号: 6486293
• 负责人: ANDREW Lurie SALZMAN
• 金额: $ 115.22万
• 依托单位: INOTEK PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6486293
• 关键词: Callithricidae; antiinflammatory agents; catalyst; dogs; drug design /synthesis /production; drug metabolism; drug screening /evaluation; enzyme inhibitors; free radical oxygen; gastrointestinal agents; guanidines; histology; histopathology; inflammatory bowel diseases; laboratory rat; nitric oxide synthase; oral administration; peroxynitrites; pharmacokinetics

DESCRIPTION (provided by applicant): Current treatment of inflammatory bowel disease (IBD) is of limited efficacy, as there are no entirely non-toxic pharmaceuticals that totally halt or reverse the progression of IBD. To address this need, Inotek is developing a series of novel anti-colitic agents that detoxify peroxynitrite, a potent oxidant formed in the intestinal mucosa of ulcerative colitis and Crohn?s Disease. Using a murine dextran sulfate model of enterocolitis, we have determined that our lead peroxynitrite decomposition catalyst, FP15, profoundly reduced bloody diarrhea, gross and microscopic histologic injury, lipid peroxidation, and weight loss and increased colon length and survival. In the Phase II SBIR, we intend to demonstrate that the in vivo toxicologic profile of FP15 meets FDA standards for progression to clinical studies. Specific Aim #1: Kilogram level production of FP15. Pre-clinical evaluation of FP15, including toxicology, metabolism, and pharmacokinetic studies, requires process scale-up to produce kilogram scale GLP-grade material. Specific Aim #2: Determine the in vivo pharmacokinetics, distribution, bioavailabllity, metabolism, and excretion (ADME) of FP15 in rats and canines. Specific Aim #3: Determine the biochemical, hematologic, and histopathologic toxicology profile of FP15. Definitive chronic toxicity studies wifi provide a comprehensive behavioral, biochemical, and histopathologic profile These studies will provide the foundation for clinical testing, commercial development, and first market entry of an ultrapotent peroxynitrite decomposition catalyst for therapy of IBD. PROPOSED COMMERCIAL APPLICATION: The annual domestic impact of IBD on the health care market is estimated at > $1 billion. The worldwide market in IBD (developed countries only) is four times larger. Given the absence of a specific and completely effective therapy, Inotek anticipates market acceptance to be achieved rapidly, at high levels of penetration, and with a high sustained price point ($1000 per patient per year). Estimated worldwide gross sales revenues after market entry and maturation (ca. 4 years after FDA approval) equal $800 million (anual).

描述（由申请人提供）：目前炎症性肠病（IBD）的治疗效果有限，因为没有完全无毒的药物可以完全阻止或逆转 IBD 的进展。为了满足这一需求，Inotek 正在开发一系列新型抗结肠药物，这些药物可以解毒过氧亚硝酸盐，过氧亚硝酸盐是一种在肠道粘膜中形成的强氧化剂。 溃疡性结肠炎和克罗恩病。使用鼠小肠结肠炎硫酸葡聚糖模型，我们确定我们的铅过氧亚硝酸盐分解催化剂 FP15 可以显着减少血性腹泻、肉眼可见的组织学损伤、脂质过氧化和体重减轻，并增加结肠长度和存活率。在第二阶段 SBIR 中，我们打算证明 FP15 的体内毒理学特征符合 FDA 进入临床研究的标准。具体目标#1：FP15 的公斤级生产。 FP15的临床前评估，包括毒理学、代谢和药代动力学研究，需要工艺放大以生产公斤级 GLP 级材料。具体目标#2：确定 FP15 在大鼠和犬科动物中的体内药代动力学、分布、生物利用度、代谢和排泄 (ADME)。具体目标#3：确定 FP15 的生化、血液学和组织病理学毒理学特征。确定性慢性毒性研究 wifi 提供全面的行为、生化和组织病理学概况 这些研究将为临床测试、 用于治疗 IBD 的超强过氧亚硝酸盐分解催化剂的商业开发和首次进入市场。 拟议的商业应用：IBD 对医疗保健市场的年度国内影响估计超过 10 亿美元。 IBD 的全球市场（仅限发达国家）是其四倍。 鉴于缺乏具体且完全有效的治疗方法，Inotek 预计将以高渗透率和高持续价格点（每年每位患者 1000 美元）迅速获得市场接受。市场进入和成熟后（FDA 批准后约 4 年）预计全球总销售收入相当于 8 亿美元（年度）。