Novel PARS inhibitor for therapy of colitis

用于治疗结肠炎的新型 PARS 抑制剂

• 批准号: 6337327
• 负责人: PRAKASH G JAGTAP
• 金额: $ 109.21万
• 依托单位: INOTEK PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-15 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6337327
• 关键词: ADP ribosylation; adenine phosphoribosyltransferase; colitis; dogs; drug adverse effect; drug design /synthesis /production; drug metabolism; drug screening /evaluation; endoscopy; enzyme inhibitors; gastrointestinal agents; histology; immunocytochemistry; inflammatory bowel diseases; laboratory rat; nonhuman therapy evaluation; pharmacokinetics

DESCRIPTION (Applicant's Abstract): 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 has invented a novel anti-colitic agent (PJ-34) that is a nanomolar-potent inhibitor of poly (ADP-ribose) synthetase (PARS). PARS are a nuclear enzyme whose activation by inflammatory oxidant stress results in energetic depletion, NF-kappa B nuclear translocation, granulocyte recruitment, and intestinal mucosal barrier dysfunction. We have shown that PARS deficient mice are virtually protected from autoimmune models of enterocolitis. In the Phase I SBIR, we have obtained proof of principle that the ultrapotent PARS inhibitor PJ-34 reverses established murine colitis, resulting in a dramatic reduction in intestinal tissue injury, inflammatory cell infiltration, mortality, and weight loss. In the Phase II SBIR, we intend to demonstrate that the in vivo toxicological profile of PJ-34 meets FDA standards for progression to clinical studies. Specific Aim #1: Scale-up synthesis of PJ-34 to kilogram batch production level. Pre-clinical evaluation of PJ-34, including toxicology, metabolism, and pharmacokinetic studies, requires process scale-up to produce kilogram scale GLP-grade material. Specific Aim #2: Determine the biochemical, hematological, and histopathologic toxicology profile of PJ-34. Range-finding toxicity studies will 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 PARS inhibitor for therapy of IBD. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE

描述（申请人的摘要）：炎症肠的当前治疗 疾病（IBD）的功效有限，因为没有完全无毒的 完全停止或逆转IBD进展的药物。解决 这种需求，Inotek发明了一种新型的抗殖民剂（PJ-34），这是一个 聚（ADP-核糖）合成酶（PARS）的纳摩尔 - 功能抑制剂。 par是一个 核酶通过炎性氧化剂应激的激活导致 能量耗竭，NF-kappa B核易位，粒细胞募集， 和肠粘膜屏障功能障碍。我们已经表明par不足 小鼠实际上是保护小肠结肠炎的自身免疫模型。在 第一阶段SBIR，我们已经获得了超霸率的原理证明 抑制剂PJ-34逆转已建立的鼠结肠炎，导致了戏剧性的 减少肠道组织损伤，炎性细胞浸润， 死亡率和体重减轻。在第二阶段SBIR中，我们打算证明 PJ-34的体内毒理学特征符合FDA的进展标准 进行临床研究。特定目标＃1：扩大PJ-34至千克的合成 批处理生产水平。 PJ-34的临床前评估，包括毒理学， 新陈代谢和药代动力学研究需要过程扩大才能产生 千克秤GLP级材料。特定目的＃2：确定生化， PJ-34的血液学和组织病理学毒理学特征。范围调查 毒性研究将提供全面的行为，生化和 组织病理学特征。这些研究将为临床提供基础 测试，商业开发和超级统一的首次市场进入 IBD治疗的抑制剂。 拟议的商业应用程序：不可用