Medicinal Chemistry/Sheppard

药物化学/谢泼德

基本信息

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
项目类别：
财政年份：
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

项目摘要

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.

项目摘要（参见说明）：特发性肺纤维化（IPF）是一种毁灭性的肺部疾病。患者三年死亡率高达 50%，而且尚无经过证实的有效治疗方法。该项目的主要目标是建立一个药物化学核心设施，支持转化研究项目，以实现我们开发 IPF 新药物疗法的共同目标。 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 beta-6 整合素激活细胞外潜在的 TGF-β，进而至少在肺泡上皮细胞中诱导进行性纤维化。部分通过诱导上皮细胞向间质细胞转化。统一我们药物开发方法的一个概念是，通过气道将药物直接递送至肺泡上皮细胞，可以最佳地靶向每种机制。吸入递送有可能最大限度地减少不良的全身效应，特别是当药物的全身利用率较低时。 Pis 项目已经确定了针对这些机制的早期筛选命中、工具化合物和先导化合物。药物化学核心将协同优化这些化合物，以获得卓越的效力、选择性和药代动力学特征（全身吸收后快速清除）通过吸入给药提高 IPF 动物模型的疗效和治疗指数。所有这些活动的目标是确定临床候选者，以便根据该 tPPG 计划的第二阶段进行 IPF 临床试验。