Inosine pro-drug: novel therapy for arthritis

肌苷前药：关节炎的新疗法

• 批准号: 6867616
• 负责人: ANDREW Lurie SALZMAN
• 金额: $ 139.67万
• 依托单位: INOTEK PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2006-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6867616
• 关键词: antiarthritic agent; arthritis therapy; combination chemotherapy; drug design /synthesis /production; drug screening /evaluation; inflammation; inosine; laboratory mouse; nonhuman therapy evaluation; pharmacokinetics; prodrugs

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is mediated by articular expression of pro-inflammatory cytokines and chemokines. We have discovered that the purine degradation product inosine exerts multiple anti-inflammatory and immunomodulatory effects via combined A2a and A3 agonism, resulting in suppressed expression of TNF-alpha, IL-1 beta, IL-12, MIP-lalpha, and IFN-gamma and enhanced expression of IL-10. We have recently developed a proprietary pro-drug of inosine, 5'-inosine monosulfate (IMS),that is more potent than inosine in vivo and shows dramatic protection against inflammatory injury. In a collagen-induced murine model of autoimmune arthritis, IMS profoundly reduced the incidence and severity of arthritis, reduced TNF-alpha and MIP-lalpha expression, and virtually eliminated neutrophil infiltration and lipid peroxidation. Coupled with the fact that free inosine is an approved OTC nutritional supplement and has an excellent record of safety in man, we envision the introduction of its prodrug IMS as a novel pharmaceutical for the treatment of RA. The Specific Aims of this Fast-Track proposal are: Phase I: Establish that IMS reverses established experimental arthritis and is effective in combination with current clinical anti-arthritic therapies. IMS will be provided to DBA/1J mice rendered arthritic by repeated injection of collagen. Our preliminary data show that introduction of IMS prior to the onset of disease is nearly fully protective. In order to establish the reversibility of established disease, IMS therapy will be introduced at day 35, after the onset of joint disease in this model system. We will also determine whether a one-week pulse of IMS therapy, initiated at day 20, will provide persistent protection against the development of arthritis in the DBA/1J model. Finally, we will establish the synergy of IMS, begun on day 20, with traditional anti-arthritic therapies, including ibuprofen and methotrexate. Progression to Phase II SBIR will require that IMS produces a 50% reduction in the severity of established collagen-induced arthritis and that IMS is synergistic with ibuprofen or methotrexate. In the Phase 2 SBIR, we will determine the pre-clinical pharmacokinetics and biochemical, hematologic, and histopathologic toxicology, and safety pharmacology profile of IMS. The proposed studies will provide the foundation for Phase la and lb clinical safety trials of IMS.

描述（由申请人提供）：风湿性关节炎（RA）由促炎细胞因子和趋化因子的关节表达介导。我们已经发现嘌呤降解产物肌苷通过组合的A2 α和A3激动作用发挥多种抗炎和免疫调节作用，导致TNF-α、IL-1 β、IL-12、MIP-1 α和IFN-γ的表达受到抑制，而IL-10的表达得到增强。我们最近开发了一种专有的肌苷前药，5 '-肌苷单硫酸盐（IMS），它在体内比肌苷更有效，并显示出对炎症损伤的显著保护作用。在胶原蛋白诱导的自身免疫性关节炎小鼠模型中，IMS显著降低关节炎的发病率和严重程度，降低TNF-α和MIP-1 α表达，并几乎消除中性粒细胞浸润和脂质过氧化。再加上游离肌苷是一种被批准的OTC营养补充剂，并且在人体中具有良好的安全性记录，我们设想将其前药IMS作为一种新型药物用于治疗RA。这个快速通道提案的具体目标是：第一阶段：确定IMS逆转已建立的实验性关节炎，并与目前的临床抗关节炎疗法联合使用有效。将IMS提供给DBA/1 J小鼠，通过重复注射胶原蛋白使其患关节炎。我们的初步数据表明，在疾病发作前引入IMS几乎是完全保护性的。为了确定已建立疾病的可逆性，将在该模型系统中关节疾病发作后的第35天引入IMS治疗。我们还将确定在第20天开始的为期一周的IMS脉冲治疗是否会在DBA/1 J模型中提供持久的保护作用，以防止关节炎的发展。最后，我们将建立IMS的协同作用，从第20天开始，与传统的抗关节炎疗法，包括布洛芬和甲氨蝶呤。进展到II期SBIR将需要IMS使已建立的胶原诱导性关节炎的严重程度降低50%，并且IMS与布洛芬或甲氨蝶呤具有协同作用。在II期SBIR中，我们将确定IMS的临床前药代动力学和生化、血液学和组织病理学毒理学以及安全药理学特征。拟定的研究将为IMS的Ia期和Ib期临床安全性试验提供基础。