Soft LXR Agonists for Idiopathic Pulmonary Fibrosis

软 LXR 激动剂治疗特发性肺纤维化

• 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
• 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

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，几乎完全发生在老年人中， 个人和有限的治疗选择。该领域的一个新兴范例是IPF由慢性 反复的损伤耗尽了肺的再生能力，导致进行性组织重塑， 导致呼吸衰竭和死亡。在最近的工作中，我们和其他人发现了 来自IPF患者、老年小鼠和实验诱导肺纤维化小鼠的肺组织经历了 一系列代谢变化，包括脂质合成的显著抑制。有了这样的理解， 我们最近探讨了恢复脂质合成是否可以降低肺纤维化的严重程度， 实验诱导的小鼠模型。为了验证这一点，我们通过全身注射一种有效的肝脏X受体， (LXR)激动剂（T0901317）对小鼠的作用。重要的是，我们发现T0901317不仅显著增加了脂质， 肺合成，但也显着减少病理变化，包括减少表达， 细胞应激标志物和肺纤维化的生物化学和组织学证据减少。重要的是 这种治疗方法的基本原理是基于对LXR激活诱导大量 不同的脂质合成基因，并且是药物发现领域中充分验证的治疗靶标。那就说： 现有的LXR激动剂在循环中高度稳定，导致许多长期副作用， 如脂肪肝和动脉粥样硬化。因此，在我们的第一阶段SBIR中，我们致力于开发一种创新的“软性药物”， 靶向LXR激活的方法。这种方法利用药物化学合成激动剂， 在肺中稳定，但在进入循环后迅速降解为无活性化合物。值得注意的是， 我们的工作导致了两个结构不同的系列化合物的开发， 活性，并在小鼠肝微粒体和血浆中表现出不稳定的性质。在第一阶段STTR提案中， 我们寻求进一步优化我们的两个系列的LXR激动剂，以找到临床前候选药物， 适合于肺内输送。为了实现这一目标，我们的建议分为三个具体目标。在Aim中 1我们将设计和合成特定的假设指导的额外的软LXR激动剂。在目标2中，我们将 评估我们的每种化合物，以确认它们在以下情况下经历快速代谢清除（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 环境最后，在目标3中，将在体内评价我们的5-7种最佳化合物诱导脂质的能力。 在急性和慢性（老年小鼠）博来霉素小鼠模型中合成和改善肺纤维化，以及 评估我们的化合物对其他组织的脱靶效应。在第一阶段STTR提案结束时，我们 预计将准备启动一个全面的药物发现和开发计划（第二阶段STTR）， 使我们能够开发吸入制剂，最终导致临床前候选药物， 有效性和安全性，直接推进IND使能研究、临床开发和 商业化