Medicinal Chemistry/Sheppard

药物化学/谢泼德

• 批准号: 8527841
• 负责人: Bradley J Backes
• 金额: $ 34.91万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8527841
• 关键词: Address; Alveolar; Animal Model; Apoptosis; Breathing; Cells; Clinical; Clinical Treatment; Clinical Trials; Collection; Core Facility; Data; Development; Drug Kinetics; Epithelial; Epithelial Cells; Face; Fibrosis; Generations; Goals; Grant; Hamman-Rich syndrome; Human; Instruction; Integrins; Lead; Lung diseases; Mediating; Mesenchymal; Methods; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacotherapy; Phase; Process; Productivity; Property; Pulmonary Fibrosis; Research Project Grants; Services; Stress; Structure of parenchyma of lung; TGFB1 gene; Testing; Therapeutic Index; Transforming Growth Factor beta; Translational Research; Triage; Work; absorption; analog; cohort; design; drug candidate; drug development; effective therapy; extracellular; high throughput screening; human tissue; improved; integrin beta6; iterative design; mortality; novel; programs; screening; tool; treatment trial

PROJECT SUMMARY (See instructions): Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease. Patients face a 50% three-year mortality rate and no proven effective therapy exists. The primary goal of this project is to establish a medicinal chemistry core facility that supports translational research projects in our shared objective to develop new drug therapies for IPF. Project Pis hypothesize that IPF is a consequence of on-going epithelial stress and apoptosis, which leads to activation of extracellular latent TGF-beta by the alpha-v beta-6 integrin on alveolar epithelial cells, which in turn induces progressive fibrosis at least in part through induction of epithelial to mesenchymal transformation. A concept that unifies our drug development approach is that each of the mechanisms can be optimally targeted by delivering drug agents directly to the alveolar epithelial cells via the airways. Delivery by inhalation has the potential to minimize unwanted systemic effects, especially when the drug agent has low systemic availability. Early screening hits, tool compounds and lead compounds that target each of these mechanisms have been identified by Project Pis. The medicinal chemistry core will work collaboratively to optimize these compounds for superior potency, selectivity and pharmacokinetic profile (rapid clearance upon systemic absorption) to increase efficacy and therapeutic index in animal models of IPF with inhaled delivery. The objective for all of these activities is to identify clinical candidates for advancement to clinical trials in IPF under the planned second phase of this tPPG.

项目总结（见说明）： 特发性肺纤维化（IPF）是一种毁灭性的肺部疾病。患者面临着50%的三年死亡率，并且没有被证明有效的治疗方法。该项目的主要目标是建立一个药物化学核心设施，支持我们共同目标中的转化研究项目，即开发IPF的新药物疗法。Pis项目假设IPF是持续上皮应激和细胞凋亡的结果，这导致肺泡上皮细胞上的α-v β-6整联蛋白激活细胞外潜伏TGF-β，进而至少部分通过诱导上皮向间充质转化诱导进行性纤维化。统一我们的药物开发方法的一个概念是，每种机制都可以通过气道将药物直接递送到肺泡上皮细胞来实现最佳靶向。通过吸入递送具有使不希望的全身作用最小化的潜力，特别是当药剂具有低全身可用性时。Pis项目已经确定了针对这些机制的早期筛选命中物、工具化合物和先导化合物。药物化学核心将协同工作，以优化这些化合物的上级效力，选择性和药代动力学特征 （全身吸收后快速清除），以增加吸入递送在IPF动物模型中的功效和治疗指数。所有这些活动的目的是确定在计划的tPPG第二阶段下推进IPF临床试验的临床候选药物。