Soft LXR Agonists for Idiopathic Pulmonary Fibrosis

软 LXR 激动剂治疗特发性肺纤维化

基本信息

批准号：
10079758
负责人：
Ross S Summer
金额：
$ 30.65万
依托单位：
FOX CHASE CHEMICAL DIVERSITY CENTER, INC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-20 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10079758
关键词：
Acute Affect Agonist Applications Grants Atherosclerosis Binding Proteins Biochemical Biological Assay Bleomycin Blood Circulation Cardiovascular system Cellular Stress Cessation of life Chemicals Chronic Cicatrix Clinical Data Development Diagnosis Disease Drug Compounding Drug usage Environment Enzymes Exhibits Exposure to FDA approved Fatty Liver Formulation Foxes Funding Goals Grant Histologic Human In Vitro Individual Inhalation Injections LXRalpha protein Laboratories Lead Lipids Liver Liver Microsomes Liver X Receptor Lung Lung diseases Metabolic Mind Modeling Mus Oral Pathology Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacotherapy Phase Pirfenidone Plasma Plasma Proteins Program Development Property Proteins Pulmonary Fibrosis Radiation Receptor Activation Reporter Respiratory Failure Risk Rodent Safety Scientist Series Serum Severities Silicon Dioxide Site Small Business Innovation Research Grant Small Business Technology Transfer Research Solubility Structure Structure of parenchyma of lung Testing Therapeutic Tissues Transcript Universities Validation Work absorption analog base clinical development commercialization design drug candidate drug development drug discovery exhaust experience gene synthesis idiopathic pulmonary fibrosis in vitro Assay in vitro activity in vivo innovation meetings member mortality mouse model novel therapeutics pre-clinical receptor regenerative scale up side effect success therapeutic target

项目摘要

Idiopathic pulmonary fibrosis (IPF) is a highly aggressive lung disease that develops almost exclusively in older individuals and has limited treatment options. An emerging paradigm in the field is that IPF results from chronic repetitive insults that exhaust the lung’s regenerative capacity, causing progressive tissue remodeling that leads to respiratory failure and death in the vast majority of patients. In recent work, we and others have uncovered that lung tissues from IPF patients, old mice and mice with experimentally-induced pulmonary fibrosis undergo a host of metabolic changes, including a marked suppression of lipid synthesis. With this understanding in mind, we recently explored whether restoring lipid synthesis can reduce the severity of pulmonary fibrosis in experimentally-induced mouse models. To test this, we delivered by systemic injection a potent Liver-X Receptor (LXR) agonist (T0901317) to mice. Importantly, we found that T0901317 not only significantly augmented lipid synthesis in the lung but also markedly reduced pathology changes, including decreasing the expression of cellular stress markers and decreasing biochemical and histological evidence of lung fibrosis. Importantly, the rationale for this therapeutic approach is based on the firm understanding that LXR activation induces a host of different lipid synthesis genes and is a well-validated therapeutic target in the drug discovery field. That said, existing LXR agonists are highly stable in the circulation, contributing to numerous long-term side effects such as fatty liver and atherosclerosis. Therefore, in our Phase I SBIR we worked to develop an innovative "soft drug" approach to targeting LXR activation. This approach utilizes medicinal chemistry to synthesize agonists that work robustly in the lung but become rapidly degraded to inactive compounds upon entry into the circulation. Notably, our work has led to the development of two structurally diverse series of compounds that possess LXR agonist activity and exhibit unstable properties in mouse liver microsomes and plasma. In this Phase I STTR proposal, we seek to further optimize our two series of LXR agonists in order to find preclinical candidates that are optimally suited for intrapulmonary delivery. To achieve this goal, our proposal is divided into three Specific Aims. In Aim 1 we will design and synthesize specific hypothesis-directed additional soft LXR agonists. In Aim 2, we will evaluate each of our compounds to confirm that they undergo rapid metabolic clearance (t1/2 < 10 mins) upon absorption into the circulation using mouse and human plasma and liver microsomes to mimic the in vivo environment. Finally, in Aim 3, 5-7 of our best compounds will be evaluated in vivo for their ability to induce lipid synthesis and ameliorate pulmonary fibrosis in acute and chronic (old mice) bleomycin mouse models, and assess off-target effects of our compounds on other tissues. At the end of this Phase I STTR proposal, we expect to be poised to initiate a full-fledged drug discovery and development program (Phase II STTR) that will enable us develop inhalation formulations that ultimately lead to preclinical drug candidates with suitable efficacy and safety properties to advance directly to IND enabling studies, clinical development and commercialization.

特发性肺纤维化（IPF）是一种高度侵袭性的肺部疾病，几乎只发生于老年人该领域的一个新兴范例是 IPF 是由慢性疾病引起的。重复的损伤会耗尽肺部的再生能力，导致进行性组织重塑，从而导致在最近的工作中，我们和其他人发现了导致绝大多数患者呼吸衰竭和死亡的原因。 IPF 患者、老年小鼠和实验性肺纤维化小鼠的肺组织发生考虑到这一点，许多代谢变化，包括脂质合成的显着抑制，我们最近探讨了恢复脂质合成是否可以减轻肺纤维化的严重程度为了测试这一点，我们通过全身注射强效的肝脏-X 受体。重要的是，我们发现 T0901317 不仅显着增加了脂质。肺中的合成，而且还显着减少病理变化，包括减少表达细胞应激标志物和减少肺纤维化的生化和组织学证据。这种治疗方法的基本原理是基于对 LXR 激活会诱导一系列不同的脂质合成基因，是药物发现领域经过充分验证的治疗靶点。现有的 LXR 激动剂在循环中高度稳定，导致许多长期副作用，例如因此，在我们的 I 期 SBIR 中，我们致力于开发一种创新的“软药”。靶向 LXR 激活的方法该方法利用药物化学来合成有效的激动剂。值得注意的是，在肺中强烈，但在进入循环后迅速降解为无活性的化合物。我们的工作导致了两个结构不同系列的具有 LXR 激动剂的化合物的开发在小鼠肝微粒体和血浆中表现出活性和不稳定特性。我们寻求进一步优化我们的两个系列 LXR 激动剂，以便找到最佳的临床前候选药物为了实现这一目标，我们的建议分为三个具体目标。 1 我们将设计并合成特定假设导向的额外软 LXR 激动剂在目标 2 中，我们将。评估我们的每种化合物，以确认它们经过快速代谢清除（t1/2 < 10 分钟）使用小鼠和人血浆和肝微粒体模拟体内吸收进入循环最后，在目标 3 中，我们将在体内评估我们最好的 5-7 种化合物诱导脂质的能力。合成并改善急性和慢性（老年小鼠）博莱霉素小鼠模型中的肺纤维化，以及在第一阶段 STTR 提案结束时，我们评估了我们的化合物对其他组织的脱靶效应。预计准备启动一项全面的药物发现和开发计划（第二阶段 STTR），该计划将使我们能够开发出吸入制剂，最终产生具有合适的临床前候选药物功效和安全性可直接推进 IND 的研究、临床开发和商业化。