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（申请人摘要）：目前炎症性肠的治疗