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，几乎只在老年人发病。 个人，治疗选择有限。该领域的一个新兴范式是，IPF是慢性 反复侮辱，耗尽肺的再生能力，导致进行性组织重塑，从而导致 导致绝大多数患者呼吸衰竭和死亡。在最近的工作中，我们和其他人发现了 IPF患者、老年小鼠和实验性肺纤维化小鼠的肺组织 一系列新陈代谢变化，包括显著抑制脂质合成。有了这样的理解， 我们最近探索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。为了测试这一点，我们通过全身注射一种有效的肝X受体 (LXR)激动剂(T0901317)给小鼠。重要的是，我们发现T0901317不仅显著增加了血脂 在肺内合成，也明显减少病理变化，包括减少表达 细胞应激标志物和肺纤维化的生化和组织学证据的减少。重要的是， 这种治疗方法的基本原理是基于这样一种坚定的理解，即LXR激活会诱导一系列 不同的脂质合成基因，是药物发现领域公认的治疗靶点。也就是说， 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 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“软药物” 针对LXR激活的方法。这种方法利用药物化学来合成有效的激动剂。 在肺中很强健，但进入循环后迅速降解为不活跃的化合物。值得注意的是， 我们的工作导致开发了两个结构不同的系列化合物，它们具有LXR激动剂 在小鼠肝微粒体和血浆中表现出活性和不稳定的性质。在这份第一阶段的STTR提案中， 我们寻求进一步优化我们的两个系列LXR激动剂，以找到临床前最佳候选药物 适合肺内给药。为了实现这一目标，我们的建议分为三个具体目标。在AIM 1我们将设计和合成特定的假设导向的附加软LXR激动剂。在目标2中，我们将 评估我们的每一种化合物以确认它们经过快速代谢清除(t1/2和lt；10分钟) 利用小鼠和人血浆和肝脏微粒子模拟体内吸收进入循环 环境。最后，在目标3、5-7中，我们将对我们最好的化合物进行体内评估，以确定它们诱导脂质的能力。 合成和改善急性和慢性(老龄小鼠)博莱霉素小鼠模型的肺纤维化，以及 评估我们的化合物对其他组织的非靶向影响。在这项第一阶段建议的最后阶段，我们 预计将启动一个全面的药物发现和开发计划(第二阶段STTR)，该计划将 使我们能够开发吸入剂配方，最终导致临床前候选药物具有合适的 有效性和安全性特性直接进入IND使能研究、临床开发和 商业化。