Novel PARS inhibitor for therapy of colitis

描述(申请人摘要)：目前炎症性肠病的治疗方法 疾病(IBD)疗效有限，因为没有完全无毒的 完全阻止或逆转IBD进展的药物。致信地址 在这种需求下，伊诺克发明了一种新型的抗结肠剂(PJ-34)，它是一种 纳摩尔有效的聚(ADP-核糖)合成酶抑制剂(PARS)。PAR是一种 由炎性氧化应激激活导致的核酶 能量耗竭，核因子-kappaB核转位，粒细胞募集， 和肠粘膜屏障功能障碍。我们已经证明了PAR是有缺陷的 小鼠几乎可以免受小肠结肠炎的自身免疫模型的影响。在 第一阶段SBIR，我们已经得到了超高能Pars的原理证明 抑制剂PJ-34逆转小鼠结肠炎，导致戏剧性的 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 到临床研究。具体目标1：放大合成PJ-34至千克 批量生产水平。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工艺放大才能生产 千克级GLP级材料。具体目标2：测定生化指标， PJ-34的血液学、组织病理学毒理学特征。测距 毒性研究将提供全面的行为、生化和 组织病理学特征。这些研究将为临床应用奠定基础。 超强PAR的测试、商用开发和首次进入市场 治疗IBD的抑制剂。 建议的商业应用：不可用

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