Development of small molecule TLR5 inhibitors for rheumatoid arthritis therapy

开发用于类风湿性关节炎治疗的小分子 TLR5 抑制剂

基本信息

批准号：
9408815
负责人：
Zachary David Aron
金额：
$ 22.46万
依托单位：
MICROBIOTIX, INC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9408815
关键词：
Achievement Acute Address Agonist American Antibodies Antibody Therapy Arthritis Attenuated Autoimmune Diseases Burkholderia CCL2 gene Cell Line Cells Chemicals Chronic Collagen-Induced Arthritis Dependovirus Development Disease Disease Progression Drug Kinetics Effectiveness Elderly Excretory function Exhibits Flagellin Goals Human Infectious Agent Injection of therapeutic agent Interleukin-6 Investigational Drugs Joints Libraries Ligands Ligation Liver Microsomes Maximum Tolerated Dose Medical Metabolism Modeling Mus Myeloid Cells NADP Older Population Osteoclasts Patients Pharmaceutical Preparations Pharmacology Study Phase Pre-Clinical Model Predictive Value Production Property Pseudomonas Reporter Research Personnel Rheumatoid Arthritis Role Safety Scientist Series Solubility Specificity Structure Structure-Activity Relationship Swelling TLR4 gene TLR5 gene TLR7 gene TNF gene Therapeutic Toxicology absorption analog aqueous arthritis therapy base bone bone erosion compare effectiveness cytotoxicity disability drug development effective therapy high throughput screening in vivo indexing inhibitor/antagonist joint destruction liquid chromatography mass spectrometry macrophage novel novel therapeutics peripheral blood pre-clinical scaffold screening small molecule

项目摘要

Abstract. Approximately 2.5 million Americans have rheumatoid arthritis (RA), which is one of the most common chronic autoimmune disorders in the older population. There is no cure for RA, and up to 40% of patients do not respond to current therapies. As a result, disease progression leads to joint destruction and severe disability in the elderly. Therefore, the identification of a novel therapeutic strategy used alone or in combination with existing therapies would resolve a critical barrier in RA treatment. The overall goal of this project is to address this unmet medical need by developing novel small molecule drugs for RA therapy. Our strategy is to build upon two new discoveries: (a) the important role of the toll-like receptor 5 (TLR5) in RA, and (b) a novel chemical series of small molecule TLR5 inhibitors. Preliminary studies revealed that TLR5 is highly elevated in RA myeloid cells as compared to normal myeloid cells, and its expression closely correlates with RA disease activity score (DAS28). Furthermore, ligation of TLR5 to its natural ligand expressed in the joints transforms RA peripheral blood (PB) myeloid cells into proinflammatory M1 macrophages and mature osteoclasts. In mice, systemic and local injection of a TLR5 agonist exacerbates joint swelling and bone erosion. Conversely, anti- TLR5 antibody (Ab) therapy attenuates collagen induced arthritis (CIA) joint inflammation and bone destruction. Coincident with these studies, collaborators discovered small molecule TLR5 inhibitors that antagonize the interaction between TLR5 and its agonist, flagellin, from bacterial infectious agents including Pseudomonas and Burkholderia. Several validated hits from the screen are effective in RA PB myeloid cells. In particular, a 2-iminobenzimidazolene (IBZ) series of compounds abrogates RA M1 macrophage differentiation and osteoclast maturation more effectively than does anti-TNF Ab, anti-IL-6R Ab or a TLR4 antagonist, and several analogs reduced flagellin induced TNF, IL-6 and CCL2 production by up to 70% in RA PB myeloid cells with low cytotoxicity, yielding a selectivity index of >10 and responsive structure–activity relationships (SAR) that will guide further chemical optimization. All three active analogs displayed good stability (90%, 84%, and 74%) in the presence of mouse liver microsomes + NADPH, and the aqueous solubility of all 3 analogs was in excess of 400 µM. In Phase I of this translational drug development project, the IBZ series will be chemically optimized to maximize potency and selectivity as well as drug-like absorption, distribution, metabolism and excretion (ADME) properties, and the mechanism of action together with the target specificity will be determined for the IBZ series. Other compounds from the TLR5 inhibition screen at MBX will serve as backup scaffolds for this project. In Phase II, in vivo-validated leads and a preclinical candidate will be identified from the IBZ series by formulating and evaluating prioritized analogs in mice to determine the maximum tolerated dose, pharmacokinetics and efficacy in a murine collagen-induced arthritis model. In Phase III, the effectiveness of the preclinical candidate will be evaluated in comparison with other currently available therapies using acute and chronic RA preclinical models, and Investigational New Drug (IND) enabling toxicology and safety pharmacology studies will be carried out.

抽象的。大约 250 万美国人患有类风湿性关节炎 (RA)，这是最常见的慢性疾病之一老年人群中的自身免疫性疾病 RA 无法治愈，高达 40% 的患者无法治愈。结果，疾病进展导致关节破坏和严重残疾。因此，需要确定一种单独使用或联合使用的新治疗策略。现有疗法将解决 RA 治疗中的一个关键障碍。该项目的总体目标是解决这一问题。我们的策略是通过开发用于 RA 治疗的新型小分子药物来满足这一未满足的医疗需求。两项新发现：(a) Toll 样受体 5 (TLR5) 在 RA 中的重要作用，以及 (b) 一种新的化学系列小分子TLR5抑制剂初步研究显示TLR5高度升高。与正常骨髓细胞相比，其表达与 RA 疾病密切相关此外，TLR5 与其在关节中表达的天然配体的连接会改变 RA。在小鼠中，外周血 (PB) 骨髓细胞转化为促炎性 M1 巨噬细胞和成熟破骨细胞。局部注射 TLR5 激动剂会加重关节肿胀和骨侵蚀。 TLR5 抗体 (Ab) 疗法可减轻胶原诱导的关节炎 (CIA) 关节炎症和骨骼与这些研究同时发生的是，合作者发现了小分子 TLR5 抑制剂。拮抗 TLR5 与其激动剂鞭毛蛋白之间的相互作用，这些感染因子包括假单胞菌和伯克霍尔德杆菌经过筛选，对 RA PB 骨髓细胞有效。特别是，2-亚氨基苯并咪唑啉 (IBZ) 系列化合物可消除 RA M1 巨噬细胞比抗 TNF Ab、抗 IL-6R Ab 或 TLR4 更有效地分化和破骨细胞成熟拮抗剂和几种类似物可将 RA 中鞭毛蛋白诱导的 TNF、IL-6 和 CCL2 的产生减少高达 70% PB 骨髓细胞具有低细胞毒性，选择性指数 >10 且具有响应性结构活性关系（SAR）将指导进一步的化学优化所有三种活性类似物都表现出良好的效果。在小鼠肝微粒体 + NADPH 和水相存在下的稳定性（90%、84% 和 74%）在该转化药物开发项目的第一阶段，所有 3 种类似物的溶解度均超过 400 µM。 IBZ 系列将进行化学优化，以最大限度地提高效力和选择性以及药物般的吸收，分布、代谢和排泄 (ADME) 特性以及作用机制以及 IBZ 系列的其他化合物的靶标特异性将在 TLR5 抑制筛选中确定。 MBX 将作为该项目第二阶段的后备支架，提供体内验证的先导药物和临床前药物。候选者将通过在小鼠中制定和评估优先类似物来从 IBZ 系列中确定确定小鼠胶原诱导性关节炎的最大耐受剂量、药代动力学和疗效在第三阶段，将与其他候选药物进行比较来评估临床前候选药物的有效性。目前可用的使用急性和慢性 RA 临床前模型的疗法以及研究性新药（IND）将进行毒理学和安全药理学研究。