Blocking a novel cytokine signaling pathway for the treatment of rheumatoid arthr

描述（由申请人提供）：尽管在类风湿性关节炎（RA）（一种影响250万美国人的破坏性自身免疫性疾病，导致关节和周围组织的慢性炎症）的管理方面取得了显著进展，但该治疗领域未满足需求的差距仍然很大。首先，几乎50%的患者对最先进的生物制剂（如Remicade和Enbrel）的主要治疗没有充分反应，这些生物制剂靶向个体促炎细胞因子。人们认识到，这些治疗失败可能与细胞因子网络内的功能冗余有关。此外，目前的RA药物通过抑制免疫反应的多个轴起作用，从而显着增加机会性感染的风险。治疗费用相对较高， 侵入性（静脉内、皮下或关节内）给药途径也是标准治疗RA生物制剂的显著缺点之一。 一种潜在的治疗类风湿性关节炎的新策略，以维持血管完整性和最小的整体免疫抑制为中心，为本项目提供了理论基础。血管反应在类风湿关节炎病理生理学中的重要作用已被充分证实。由滑膜组织中的促炎刺激物（包括细胞因子）诱导的血管内皮屏障破坏和病理性血管生成在类风湿性炎症和关节破坏中起关键作用。我们提出的信号模型表明，抑制剂的小GTd6 Arf6将阻止血管通透性过高和血管生成的收敛点下游从多个“关节炎”受体，而离开NF？B级联反应，控制免疫反应的其他方面，基本上完好无损。在我们看来，这种治疗方法首先可以通过克服与细胞因子冗余相关的限制来改善对治疗的反应性，其次可以通过最小化免疫抑制作用来改善药物安全性。 在I期SBIR中鉴定的首个同类化学系列小分子Arf 6抑制剂 研究被提议作为II期药物化学驱动的电极导线优化计划的起点。它的主要代表在细胞模型中具有稳定细胞屏障和抗血管生成的活性，最重要的是， 在胶原诱导的关节炎的小鼠模型中的功效与Enbrel相当。预计拟议的努力将产生具有适当药代动力学和毒理学特征的用于临床前IND使能研究的口服生物可利用候选物。Arf 6功能的药理学调节在与血管渗漏相关的其他适应症的背景下也可能具有治疗潜力，如使用湿性年龄相关性黄斑变性和炎症诱导的急性肺损伤的体内模型的初步疗效研究的有希望的结果所证明的。

DESCRIPTION (provided by applicant): In spite of remarkable progress in management of rheumatoid arthritis (RA), a devastating autoimmune disease that affects 2.5 million Americans causing chronic inflammation of joints and surrounding tissues, the gap of unmet needs in this therapeutic field remains wide open. First of all, almost 50% of the patients do not respond adequately to the most advanced mainstay treatment with the biologics, such as Remicade and Enbrel, that target individual pro-inflammatory cytokines. It is recognized that these therapeutic failures may be related to the functional redundancies within the cytokine network. Furthermore, the current RA medications act by suppressing multiple axes of immune response thereby markedly elevating risk of opportunistic infections. Both the relatively high cost of treatment and invasive (intravenous, subcutaneous or intra-articular) route of administration also contribute to the list of notable drawbacks for the standard-of-care RA biologics. A potential new strategy for the treatment of rheumatoid arthritis, which centers on maintaining vascular integrity with minimal overall immunosuppression, provides the rationale for the present project. The essential roles of vascular response in RA pathophysiology are well documented. Both disruption of vascular endothelial barrier and pathologic angiogenesis that are induced by pro-inflammatory stimuli including cytokines in synovial tissue play key roles in rheumatoid inflammation and destruction of joints. Our proposed signaling model suggests that inhibitors of small GTPase Arf6 would block vascular hyperpermeability and angiogenesis at a convergence point downstream from multiple "pro-arthritic" receptors while leaving the NF?B cascade, which governs other aspects of immune response, essentially intact. In our view, such a therapeutic approach may allow, first, to improve responsiveness to the treatment by overcoming the limitation associated with cytokine redundancies, and, second, to improve drug safety by minimizing immunosuppressive effects. The first in-class chemical series of small molecule Arf6 inhibitors identified in the Phase I SBIR study is proposed as a starting point for the medicinal chemistry-driven lead optimization program in Phase II. Its top representatives have been characterized by both cell barrier-stabilizing and anti-angiogenic activities in cellular models and, most importantly, by therapeutic efficacy comparable to that of Enbrel in a mouse model of collagen-induced arthritis. The proposed efforts are projected to yield orally bioavailable candidates for pre- clinical IND enabling studies with appropriate pharmacokinetic and toxicology profiles. The pharmacological modulation of Arf6 function may also have therapeutic potential in the context of other indications associated with vascular leak as evidenced by the promising outcome of preliminary efficacy studies using in vivo models of wet age-related macular degeneration and inflammation-induced acute lung injury.