Novel PARS inhibitor for therapy of colitis

用于治疗结肠炎的新型 PARS 抑制剂

• 批准号: 6517476
• 负责人: PRAKASH G JAGTAP
• 金额: $ 85.71万
• 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 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6517476
• 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（申请人摘要）：炎症性肠病的当前治疗 疾病（IBD）的疗效有限，因为没有完全无毒的 这些药物可以完全阻止或逆转IBD的进展。解决 为了满足这一需求，Inotek发明了一种新型抗结肠炎剂（PJ-34）， 聚（ADP-核糖）合成酶（PARS）的纳摩尔有效抑制剂。部分是一个 一种核酶，被炎性氧化应激激活后， 能量消耗，NF-κ B核转位，粒细胞募集， 和肠粘膜屏障功能障碍。我们已经证明， 小鼠实际上被保护免于小肠结肠炎的自身免疫模型。在 第一阶段SBIR，我们已经获得了原理证明，超幂PARS 抑制剂PJ-34逆转已建立的鼠结肠炎，导致显著的 减少肠组织损伤，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的体内毒理学特性符合FDA的进展标准 临床研究。具体目标#1：将PJ-34的规模放大合成至千克 批量生产水平。PJ-34的临床前评价，包括毒理学， 代谢和药代动力学研究，需要工艺放大， 公斤级GLP级材料。具体目标#2：确定生物化学， PJ-34血液学和组织病理学毒理学特征。范围探索 毒性研究将提供一个全面的行为，生化， 组织病理学特征。这些研究将为临床提供基础 超高效PARS的测试、商业开发和首次进入市场 用于治疗IBD抑制剂。 拟议商业应用：不可用