Novel Small Molecule Adjuvants to Drug-eluting Stents
药物洗脱支架的新型小分子佐剂
基本信息
- 批准号:7395130
- 负责人:
- 金额:$ 29.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:3-DimensionalAccelerationAdjuvantApoptosisBackBenchmarkingBinding SitesBiodistributionBiological AssayBiologyBlood VesselsC57BL/6 MouseCapitalCardiologyCell DeathCell ProliferationChemicalsClassClinicClinicalClinical TrialsCompatibleConsultCoupledCytoskeletonDataDepthDevelopmentDevice or Instrument DevelopmentDoseDrug DesignDrug effect disorderDrug usageEndothelial CellsEvaluationFibroblastsFutureGene ProteinsGoalsGrowth FactorGrowth Factor InteractionHeadHealedHemoglobinHepatocyte Growth FactorHumanHyperplasiaImplantIntellectual PropertyInternationalKentuckyKnowledgeLaboratoriesLawyersLeadLegal patentLibrariesManufacturer NameMediationMedicalMedical DeviceMedicineMorbidity - disease rateMyocardialNeoplasm MetastasisNumbersOperative Surgical ProceduresPaperPathway interactionsPeripheralPhage DisplayPharmaceutical ChemistryPharmaceutical PreparationsPhasePhase II Clinical TrialsPhysiologicalPlagueProtein ChemistryProteinsProteomicsProto-Oncogene Protein c-metPublishingRateResearchResourcesSafetyScientistSideSignal TransductionSmall Business Funding MechanismsSmall Business Innovation Research GrantSpecificityStagingStentsSurgeonSystemTechnologyTestingTherapeuticThrombosisTissuesTrainingTranslational ResearchTubeTyrosine Kinase DomainUniversitiesWisconsinangiogenesisbasecardiovascular injurycostdesignexperiencehealinghuman MET proteinin vivoin vivo Modelinterestlocal drug deliverymatrigelmedical schoolsmembermigrationmimeticsmolecular modelingmortalitynovelpharmacophorepre-clinicalprofessorprogramsrestenosisscaffoldsmall moleculesymposiumthree dimensional structuretoolvascular smooth muscle cell proliferation
项目摘要
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(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)促进内皮细胞的增殖和迁移。在药物洗脱支架上使用SF/HGF涂层作为佐剂的可行性因与基因和蛋白质治疗相关的问题而变得复杂。Angion Biomedica正在开发调节SF/HGF/c-Met信号以达到治疗优势的小分子。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,利用包括噬菌体展示、三维分子建模、蛋白质化学和临床前生物学在内的产物发现引擎,我们鉴定了一种具有潜在SF/HGF样生物活性的二氮杂氮-1(2H)-酮支架。合理的药物设计驱动的侧链在这一支架上的添加导致了Ang 1170的鉴定,这是该类中的第一个小分子类药物成员。初步研究表明,Ang 1170可激活SF/HGF/c-Met途径,刺激内皮细胞增殖,保护内皮细胞免于死亡。重要的是,Ang 1170对成纤维细胞或血管平滑肌细胞的增殖没有影响。自那以后,我们围绕二氮杂氮-1(2H)-一个由21种具有潜在SF/HGF样生物活性的化合物组成的结构文库构建了一个结构文库,最终目标是鉴定一种SF/HGF样小分子,它不仅具有生物有效性和有效性,而且具有与人类使用兼容的安全性。这一第一阶段应用的目标是将靶向蛋白质组学和药物化学与体内生物功效分析相结合,以确定该二氮杂氮-1(2H)-酮库中用于刺激内皮细胞增殖计划的候选化合物。从这一第一阶段计划中脱颖而出的两名候选者随后将被提交给深入的临床前SBIR第二阶段研究,包括支架内再狭窄的体内模型、生物分布研究和正式的管理/安全研究。这项研究的最终目标是将一种类似SF/HGF的小分子应用于临床,作为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性再狭窄困扰着目前批准的药物洗脱支架,仍然是导致发病率和死亡率的重要原因。一种减少再狭窄的小分子疗法具有巨大的临床益处。
项目成果
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PRAKASH NARAYAN其他文献
PRAKASH NARAYAN的其他文献
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{{ truncateString('PRAKASH NARAYAN', 18)}}的其他基金
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- 资助金额:
$ 29.55万 - 项目类别:
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