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

• 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
• 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

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。 大约有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。 老年人的自身免疫性疾病RA无法治愈，高达40%的患者无法治愈 对目前的治疗有反应。因此，疾病进展导致关节破坏和严重残疾， 老人因此，单独使用或联合使用的新的治疗策略的鉴定， 现有的疗法将解决RA治疗中的关键障碍。该项目的总体目标是解决 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。我们的战略是建立 基于两项新发现：（a）Toll样受体5（TLR 5）在RA中的重要作用，以及（B）一种新的 小分子TLR 5抑制剂的化学系列。初步研究显示，TLR 5在体内的表达水平 在RA骨髓细胞中，与正常骨髓细胞相比，其表达与RA疾病密切相关 活动评分（DAS 28）。此外，TLR 5与其在关节中表达的天然配体的连接可转化RA。 外周血（PB）髓样细胞转化为促炎性M1巨噬细胞和成熟破骨细胞。在小鼠中， 全身和局部注射TLR 5激动剂加剧了关节肿胀和骨侵蚀。相反，反 TLR 5抗体（Ab）疗法减弱胶原诱导的关节炎（CIA）关节炎症和骨 杀伤性与这些研究同时，合作者发现了小分子TLR 5抑制剂， 拮抗TLR 5与其激动剂鞭毛蛋白之间的相互作用， 假单胞菌和伯克霍尔德菌。来自筛选的几个经验证的命中在RA PB骨髓细胞中是有效的。 特别地，2-亚氨基苯并咪唑烯（IBZ）系列化合物消除RA M1巨噬细胞 与抗TNF Ab、抗IL-6 R Ab或TLR 4相比， 拮抗剂和几种类似物使RA中鞭毛蛋白诱导的TNF、IL-6和CCL 2的产生减少高达70 具有低细胞毒性的PB骨髓细胞，产生>10的选择性指数和响应性结构-活性 这些关系（SAR）将指导进一步的化学优化。所有三种活性类似物均显示良好 在小鼠肝微粒体+ NADPH和水溶液存在下的稳定性（90%、84%和74%） 所有3种类似物的溶解度均超过400 μM。在这个转化药物开发项目的第一阶段， 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样吸收， 分布、代谢和排泄（ADME）特性，以及与 将确定IBZ系列的靶特异性。来自TLR 5抑制筛选的其他化合物， MBX将作为该项目的备用脚手架。在第二阶段，体内验证的电极导线和临床前 通过在小鼠中配制和评估优先类似物， 确定小鼠胶原诱导关节炎的最大耐受剂量、药代动力学和疗效 模型在第三阶段，临床前候选药物的有效性将与其他药物进行比较， 使用急性和慢性RA临床前模型的现有疗法，以及研究性新药 (IND)将进行毒理学和安全药理学研究。