Prevention of arthritis-induced bone erosion by inhibiting osteoclast differentiation by the haloanilide, N-Methyl Dichloropropionaniline

通过卤代苯胺、N-甲基二氯丙苯胺抑制破骨细胞分化来预防关节炎引起的骨侵蚀

• 批准号: 10116621
• 负责人: John B Barnett
• 金额: $ 110.37万
• 依托单位: EXESALIBERO, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-25 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116621
• 关键词: Acute; Adult; Adverse effects; Animals; Arthritis; Autoimmunity; Biological; Biology; Blood drug level result; Bone Resorption; Calcium; Calcium Channel; Cell membrane; Cells; Child; Chronic; Climacteric; Collaborations; Collagen Arthritis; Contracts; Data; Development; Dose; Drug Formulations; Drug Kinetics; Effectiveness; Etanercept; Evolution; Excretory function; Formulation; Genetic Transcription; Goals; Home environment; Human; Humira; Immune system; Immunology; Immunotoxicology; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory Arthritis; Institution; Ion Channel; Joints; Lead; Letters; Leucocytic infiltrate; Lipids; Liposomes; Liver; Measures; Mediating; Metabolic; Metabolism; Methotrexate; Modeling; Molecular; Mus; Non-Steroidal Anti-Inflammatory Agents; Oral Administration; Osteitis; Osteoblasts; Osteoclasts; Pain; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pharmacology and Toxicology; Pharmacotherapy; Phase; Physiological; Prevention; Production; Proteins; Quality of life; Regimen; Request for Proposals; Research Contracts; Rheumatoid Arthritis; Risk; Rodent; Route; Signal Pathway; Signal Transduction; Site; Small Business Technology Transfer Research; Small Interfering RNA; Specificity; Steroids; Stimulus; Swelling; Symptoms; T-Cell Activation; T-Lymphocyte; TNF gene; Testing; Therapeutic; Toxic effect; Toxicokinetics; Trauma; Work; absorption; adalimumab; base; bone; bone erosion; combat; cost; drug candidate; drug development; experimental study; immunotoxicity; improved; in vivo; indexing; inhibitor/antagonist; joint injury; mature animal; monocyte; nanoparticle; novel; novel strategies; novel therapeutics; parenteral administration; preclinical development; preclinical study; prevent; response; sex; side effect; small molecule; small molecule inhibitor; standard of care

We are working on a new approach to treating acute arthritis based on a common pathway in the cellular infiltrates that damage bones and joints. Inflammatory arthritis disables thousands of people each year. It occurs in children and adults, after trauma and infections but most cases are idiopathic. Millions of adults live with chronic RA, which has similar features. Inflammatory arthritis often requires treatments with serious side effects. Later in arthritis, bone erosion is a major problem that causes severe pain and debilitation. There is no small molecule drug available to specifically treat arthritic bone erosion. We show that osteoclast maturation is suppressed by blocking a calcium-release activated calcium channel, called Orai. A Orai antagonist, N-methyl- 3,4-dichloropropionaniline (N-MeDCPA), suppressed osteoclast maturation and strongly suppressed collagen- induced arthritis (CIA) in mice, even after symptoms of arthritis were measureable. We propose that pharmacologically suppressing CRAC channels with N-MeDCPA will prevent bone erosion due to arthritic stimuli without major adverse effects. We hypothesize that Ca2+ signals mediated by Orai channels modulate final differentiation of osteoclasts, and that related effects on T cells might reinforce bone and joint sparing in acute arthritis. We expect toxicity of N-MeDCPA to be low when treatment is for several weeks in animals with mature immune systems. We propose comprehensive pharmacokinetic and toxicokinetic testing in addition to mechanistic experiments with Ca2+ signaling, immunology, and bone biology expertise. Phase I - AIM 1: - Drug formulation, route of administration optimization and Orai specificity. N- MeDCPA is lipid soluble. This aim will define a suitable nanoparticle (NP) or liposome formulation of N- MeDCPA for parenteral or oral administration. Drug blood levels versus ease/convenience and effectiveness will be assessed. Phase I – AIM 2: - Complete the dose-response studies of N-MeDCPA using the CIA model. Having demonstrated that N-MeDCPA can prevent bone erosion and arrest inflammation in symptomatic mice, the emphasis of this aim will be to define its effect against the standard CIA measures, arthritic index, bone erosion, volume by µCT and inflammation (swelling) using the optimized dosing regimen. Phase II - AIM 1: Pharmacology and toxicology assessment of N-MeDCPA under non-GLP and GLP conditions in vitro and in vivo. An extensive suite of tests will be performed by a contract research organization (CRO) under contract with ExesaLibero (see letter of support from Covance). Phase II - AIM 2: Determine the therapeutic-potential of N-MeDCPA. Critical to demonstrating that N- MeDCPA will improve the standard of care/quality of life, is confirmation of equal effectiveness in both sexes using SKG mice, determining its cellular specificity, checking for potential immunotoxicity of N-MeDCPA in tests not covered by the CRO and exploring possible additive/synergistic effects of N-MeDCPA in combination with other current non-biological treatments, e.g., methotrexate. We will also study the in vitro effects on human cells to avoid the pitfall of rodent-human physiological differences. Phase II - AIM 3: Assess the specificity and mechanism of action of N-MeDCPA. We will assess the action of the N-MeDCPA on monocyte differentiation to osteoclasts, and investigate the possible side effects on osteoblasts and its specificity for ion channels. The development of N-MeDCPA as a drug for treatment of bone erosion promises to prevent the life- changing debilitation associated with RA, effectively with low toxicity.

我们正在研究一种新的方法来治疗急性关节炎的基础上一个共同的途径，在细胞 破坏骨骼和关节的渗透物。炎症性关节炎每年使成千上万的人致残。它发生 在儿童和成人中，在创伤和感染后，但大多数病例是特发性的。数百万成年人生活在 慢性类风湿性关节炎也有类似的特点。炎症性关节炎通常需要治疗严重的副作用。 在关节炎后期，骨质侵蚀是一个主要问题，导致严重的疼痛和虚弱。有不小 分子药物，专门治疗关节炎骨侵蚀。我们发现破骨细胞的成熟 通过阻断钙释放激活的钙通道，称为奥赖。一种奥赖拮抗剂，N-甲基- 3，4-二氯丙苯胺（N-MeDCPA），抑制破骨细胞的成熟和强烈抑制胶原蛋白， 诱导的关节炎（CIA），甚至在关节炎的症状可测量之后。我们建议 用N-MeDCPA抑制CRAC通道将防止由于关节炎刺激引起的骨侵蚀 没有严重的不良影响。 我们假设由奥赖通道介导的Ca 2+信号调节破骨细胞的最终分化， 对T细胞的相关影响可能会加强急性关节炎中骨和关节的保护。我们预计毒性 在具有成熟免疫系统的动物中，当治疗数周时，N-MeDCPA较低。我们提出 除了Ca 2+的机制实验外，还进行了全面的药代动力学和毒代动力学试验 信号、免疫学和骨生物学专业知识。 第一阶段-目标1：-药物配方，给药途径优化和奥赖特异性.不，不 MeDCPA是脂溶性的。该目的将限定N-甲基-N-（2-甲基-N-苯基）-N-（2-甲基）-N- 用于肠胃外或口服给药的MeDCPA。药物血药浓度与易用性/便利性和有效性将 被评估。 第一阶段-目标2：-完成使用CIA模型的N-MeDCPA的剂量反应研究。具有 证明N-MeDCPA可以预防有症状小鼠的骨侵蚀和抑制炎症， 这一目标的重点将是确定其对标准CIA指标、关节炎指数、骨侵蚀 使用优化的给药方案，通过µCT和炎症（肿胀）测量体积。 II期- AIM 1：非GLP和GLP下N-MeDCPA的药理学和毒理学评估 体外和体内条件。一个合同研究组织将进行一系列广泛的测试 (CRO)根据与ExesaLibero的合同（见Covance的支持函）。 II期- AIM 2：确定N-MeDCPA的治疗潜力。关键是要证明N- MeDCPA将改善护理标准/生活质量，证实在两性中具有同等有效性 使用SKG小鼠，测定其细胞特异性，检查试验中N-MeDCPA的潜在免疫毒性 未被CRO涵盖，并探索N-MeDCPA与 其它目前的非生物处理，例如，甲氨蝶呤我们还将研究对人体细胞的体外影响 以避免啮齿动物和人类生理差异的陷阱。 II期- AIM 3：评估N-MeDCPA的特异性和作用机制。我们将评估行动 N-MeDCPA对单核细胞向破骨细胞分化的影响，并研究其可能的副作用。 成骨细胞及其对离子通道的特异性。 N-MeDCPA作为一种治疗骨质侵蚀的药物的发展有望防止生命- 有效改变类风湿关节炎相关的虚弱症状，毒性低。