Novel Small Molecule Adjuvants to Drug-eluting Stents

药物洗脱支架的新型小分子佐剂

• 批准号: 7395130
• 负责人: PRAKASH NARAYAN
• 金额: $ 29.55万
• 依托单位: ANGION BIOMEDICA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-15 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7395130
• 关键词: 3-Dimensional; Acceleration; Adjuvant; Apoptosis; Back; Benchmarking; Binding Sites; Biodistribution; Biological Assay; Biology; Blood Vessels; C57BL/6 Mouse; Capital; Cardiology; Cell Death; Cell Proliferation; Chemicals; Class; Clinic; Clinical; Clinical Trials; Compatible; Consult; Coupled; Cytoskeleton; Data; Depth; Development; Device or Instrument Development; Dose; Drug Design; Drug effect disorder; Drug usage; Endothelial Cells; Evaluation; Fibroblasts; Future; Gene Proteins; Goals; Growth Factor; Growth Factor Interaction; Head; Healed; Hemoglobin; Hepatocyte Growth Factor; Human; Hyperplasia; Implant; Intellectual Property; International; Kentucky; Knowledge; Laboratories; Lawyers; Lead; Legal patent; Libraries; Manufacturer Name; Mediation; Medical; Medical Device; Medicine; Morbidity - disease rate; Myocardial; Neoplasm Metastasis; Numbers; Operative Surgical Procedures; Paper; Pathway interactions; Peripheral; Phage Display; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Physiological; Plague; Protein Chemistry; Proteins; Proteomics; Proto-Oncogene Protein c-met; Publishing; Rate; Research; Resources; Safety; Scientist; Side; Signal Transduction; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Specificity; Staging; Stents; Surgeon; System; Technology; Testing; Therapeutic; Thrombosis; Tissues; Training; Translational Research; Tube; Tyrosine Kinase Domain; Universities; Wisconsin; angiogenesis; base; cardiovascular injury; cost; design; experience; healing; human MET protein; in vivo; in vivo Model; interest; local drug delivery; matrigel; medical schools; member; migration; mimetics; molecular modeling; mortality; novel; pharmacophore; pre-clinical; professor; programs; restenosis; scaffold; small molecule; symposium; three dimensional structure; tool; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): Currently approved drug-eluting stents are plagued by late-stage thrombosis and delayed restenosis. Acceleration of stent re-endothelialization can suppress neointimal hyperplasia, promote healing of the vessel wall, and decrease restenosis rates. Scatter factor/hepatocyte growth factor (SF/HGF) promotes endothelial cell proliferation and migration. Feasibility of using an SF/HGF coat as an adjuvant on drug-eluting stents is compounded by issues relating to gene and protein therapy. Angion Biomedica is pursuing the development of small molecules that regulate SF/HGF/c-Met signaling to therapeutic advantage. Based on the 3-dimensional structure of the ATP-binding site of the SF/HGF receptor c-Met's tyrosine kinase domain and using a product discovery engine comprising phage display, 3-dimensional molecular modeling, protein chemistry and preclinical biology, we have identified a phthalazin-1 (2H)-one scaffold with potential SF/HGF-like bioactivity. Rational drug design-driven side-chain additions onto this scaffold led to the identification of Ang 1170, the first small molecule drug-like member within this class. Preliminary data indicate that Ang 1170 activates the SF/HGF/c-Met pathway, stimulates endothelial cell proliferation, and protects against endothelial cell death. Importantly, Ang 1170 has no effects on fibroblast or vascular smooth muscle cell proliferation. We have since constructed a structural library around the phthalazin-1 (2H)-one scaffold comprising 21 compounds with potential SF/HGF-like bioactivity, the eventual goal being the identification of an SF/HGF-like small molecule that is not only bioeffiacious and potent but also carries a safety profile compatible with human use. The goal of this Phase I application is to couple targeted proteomics and medicinal chemistry to an in vivo bioefficacy assay in order to identify lead and fallback candidates within this phthalazin-1 (2H)-one library for stimulation of the endothelial cell proliferation program. The two candidates emerging from this Phase I program will then be submitted to in-depth, preclinical SBIR Phase II studies comprising in vivo models of in-stent restenosis, biodistribution studies, and formal regulatory/safety studies. The ultimate goal of this study is to advance an SF/HGF-like small molecule to the clinic for use as an adjuvant coat on currently used drug-eluting stents.Late stage thrombosis and delayed restenosis plague currently approved drug-eluting stents and remains a significant cause of morbidity and mortality. A small molecule therapeutic that reduces restenosis has tremendous clinical benefit.

描述（由申请人提供）：目前批准的药物洗脱支架受到晚期血栓形成和延迟再狭窄的困扰。加速支架再内皮化可抑制新生内膜增生，促进血管壁愈合，降低再狭窄率。分散因子/肝细胞生长因子（SF/HGF）促进内皮细胞增殖和迁移。使用SF/HGF涂层作为药物洗脱支架上的佐剂的可行性与基因和蛋白质治疗相关的问题复杂化。Angion Biomedica正在开发调节SF/HGF/c-Met信号传导的小分子，以获得治疗优势。基于SF/HGF受体c-Met酪氨酸激酶结构域的ATP结合位点的三维结构，并使用包括噬菌体展示、三维分子模拟、蛋白质化学和临床前生物学的产品发现引擎，我们鉴定了具有潜在SF/HGF样生物活性的酞嗪-1（2 H）-酮支架。合理的药物设计驱动的侧链添加到该支架上导致了Ang 1170的鉴定，这是该类中的第一个小分子药物样成员。初步数据表明，Ang 1170激活SF/HGF/c-Met通路，刺激内皮细胞增殖，并防止内皮细胞死亡。重要的是，Ang 1170对成纤维细胞或血管平滑肌细胞增殖没有影响。此后，我们构建了一个结构库，包括21个具有潜在SF/HGF样生物活性的化合物，最终目标是鉴定SF/HGF样小分子，其不仅具有生物有效性和有效性，而且具有与人类使用相容的安全性。该I期申请的目标是将靶向蛋白质组学和药物化学与体内生物功效测定相结合，以鉴定该酞嗪-1（2 H）-酮文库中的先导和后备候选物，用于刺激内皮细胞增殖程序。然后，将从该I期项目中获得的两个候选药物提交至深入的临床前SBIR II期研究，包括支架内再狭窄的体内模型、生物分布研究和正式的监管/安全性研究。本研究的最终目的是将SF/HGF样小分子推进临床，用作目前使用的药物洗脱支架的辅助涂层。晚期血栓形成和延迟再狭窄困扰着目前批准的药物洗脱支架，并且仍然是发病率和死亡率的重要原因。减少再狭窄的小分子治疗剂具有巨大的临床益处。