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）是一种高度侵略性的肺部疾病，几乎完全在较旧的情况下发展个人，治疗方案有限。该领域的新兴范式是IPF由慢性产生重复的侮辱会耗尽肺部再生能力，导致进行性组织重塑导致绝大多数患者的呼吸衰竭和死亡。在最近的工作中，我们和其他人发现了 IPF患者，老鼠和具有实验诱导的肺纤维化的小鼠的肺组织经历许多代谢变化，包括对脂质合成的明显抑制。考虑到这种理解，我们最近探讨了恢复脂质合成是否可以减少肺纤维化的严重程度实验引起的小鼠模型。为了测试这一点，我们通过全身注入潜在的liver-X受体传递（LXR）激动剂（T0901317）到小鼠。重要的是，我们发现T0901317不仅显着增强了脂质肺中的合成，但也显着降低了病理变化，包括降低细胞应力标记并减少肺纤维化的生化和组织学证据。重要的是，这种治疗方法的基本原理是基于坚定的理解，即LXR激活诱导了许多不同的脂质合成基因，是药物发现领域中有验证的治疗靶标。就是说，现有的LXR激动剂在循环中非常稳定，导致了许多长期副作用作为脂肪肝和动脉粥样硬化。因此，在我们的第一阶段，我们致力于开发创新的“软药” 靶向LXR激活的方法。这种方法利用医学化学来合成起作用的激动剂进入循环时，在肺部稳健，但在进入循环时会迅速降解为无活性化合物。尤其，我们的工作导致了具有LXR激动剂的两个结构上多样化的化合物的发展小鼠肝微粒体和血浆中的活性和表现出不稳定的特性。在这个阶段，我的sttr提案，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者适合肺内输送。为了实现这一目标，我们的建议分为三个具体目标。目标 1我们将设计和合成特定假设指导的其他软LXR激动剂。在AIM 2中，我们将评估我们的每种化合物，以确认它们会在使用小鼠和人血浆和肝微粒体抽象进入循环系统，以模仿体内环境。最后，在AIM 3，我们最好的化合物的5-7中，将在体内评估其诱导脂质的能力急性和慢性（旧小鼠）博来霉素小鼠模型中的合成和改善肺纤维化，以及评估我们化合物对其他组织的脱靶作用。在此阶段我的sttr提案结束时，我们期望被中毒启动成熟的药物发现和开发计划（II阶段STTR），该计划将使美国开发吸入配方最终导致临床前药物候选者有效性和安全性直接提高到IND促进研究，临床发展和商业化。