Preclinical assessment of a novel systemic drug candidate for osteoarthritic pain

摘要 骨关节炎(OA)，也称为退行性关节疾病，是一种进行性疾病，最终导致 一种功能性残疾，使其成为全球第11大最令人衰弱的疾病，也是最紧迫的疾病之一 当前的公共卫生问题。骨性关节炎最显著的临床症状是慢性关节疼痛，是渐进性的。 发病，并随着时间的推移而恶化。疼痛相关的功能损害的特征是干扰 日常活动的许多方面显著降低了生活质量。尽管有所保留，但存在争议 根据当前指南的建议，由于依赖、滥用、耐受性和毒性方面的考虑，阿片类药物是 当其他疼痛治疗方案失败时，经常开出止痛处方。消极的一面 阿片类药物的后果表明有必要为骨性关节炎疼痛控制提供替代路径选择。办公自动化是一个 多因素障碍，包括部分由白细胞介素1介导的低级别慢性炎症。 6/糖蛋白130(IL-6/gp130)级联导致基质逐渐降解和不可逆转的破坏 关节软骨。最近的研究报道，IL-6/gp130信号转导通路参与了血管内皮细胞瘤的发生发展。 炎症性病理性疼痛。此前，我们已经证明了对细胞内残留物的操纵 在gp130受体及其上下文中，特定的下游信号可以被解构以选择性地绕过 在促进有益结果的同时，这一轴心的促炎后果。我们的小组已经确定了一个 Gp130内的信号残基(Y814)，代表一个启动因子，负责高度激活 Gp130的伤害性臂和Y814的结构性消融抑制了损伤诱导的骨关节炎的发展。 为了操纵gp130下游的破坏性输出，包括那些受Y814监管的输出，我们有 合成了一类新的能够选择性失活gp130信号转导通路的小分子化合物 从而保护膝关节软骨免受基质降解，减轻大鼠和犬的疼痛 创伤后骨性关节炎的模型。通过多轮优化，我们命名为R159的模拟 显示出对gp130Y814最有效和选择性的抑制以及良好的吸收、分布 代谢和排泄(ADME)图谱。目前的拨款申请旨在系统地调查 Gp130Y814在骨性关节炎发病机制中的意义及药理作用 残留物将减轻与骨性关节炎相关的慢性疼痛。为此，我们将首先定义全身药代动力学 大鼠口服和腹腔给药后R159的参数。随后，我们将确定 全身用药R159对高血压病患者疼痛及功能行为和情感行为的影响 临床CFA诱导的踝关节骨性关节炎大鼠及全身性骨性关节炎豚鼠模型。到目前为止还没有进行过临床试验 提供了足够的证据证明任何止痛药的长期有效性，这会刺激一条途径 以促进新疗法的发展。如果有效，一种基于机制的高度选择性化合物的发现 可能会作为一种不会上瘾的高级止痛剂来影响实践。

ABSTRACT Osteoarthritis (OA), also known as degenerative joint disease, is a progressive disease that eventually leads to a functional disability making it the 11th most debilitating ailment worldwide and one of the greatest pressing current issues in public health. The most notable clinical symptom of OA is chronic joint pain that is gradual in onset and that worsens over time. The pain-related functional impairment is characterized by interference with many aspects of daily activity significantly decreasing quality of life. Despite reserved controversial recommendations by current guidelines due to dependency, abuse, tolerability and toxicity concerns, opioids are frequently prescribed for pain control when other pain management options have failed. The negative consequences of opioids evince a necessity for alternative route options for OA pain management. OA is a multifactorial disorder, which involves low-grade, chronic inflammation that is mediated, in part, by interleukin- 6/glycoprotein 130 (IL-6/gp130) cascade leading to gradual matrix degradation and irreversible destruction of articular cartilage. Recent studies have reported that IL-6/gp130 signaling is implicated in the development of inflammatory, pathological pain. Previously, we have demonstrated that manipulation of intracellular residues within gp130 receptor and its context specific downstream signaling can be deconstructed to selectively bypass the pro-inflammatory consequences of this axis while promoting beneficial outcomes. Our group has identified a signaling residue (Y814) within gp130 that represents an initiating factor responsible for the activation of a highly detrimental arm of gp130 and constitutive ablation of Y814 in mice inhibits development of injury-induced OA. To manipulate the destructive outputs downstream of gp130, including those regulated by Y814, we have synthesized a new class of small molecule compounds capable of selective inactivation of gp130 signaling and consequently protect articular cartilage in the knee from matrix degradation and reduce pain in rat and canine models of post-traumatic OA. Through multiple rounds of optimization, an analog that we termed R159 has shown the most potent and selective inhibition of gp130Y814 as well as an excellent absorption, distribution, metabolism, and excretion (ADME) profile. Current grant application is designed to systematically investigate the significance of gp130Y814 in the pathogenesis of OA and interrogate whether pharmacologically targeting this residue will attenuate OA-associated chronic pain. For this, we will first define the systemic pharmacokinetic parameters for R159 after oral and intraperitoneal administration to rats. Subsequently, we will determine the efficacy of systemically administered R159 in mitigating pain and functional and affective behaviors in a pre- clinical CFA-induced ankle OA rat and generalized OA guinea pig models. No conducted clinical trials till date have provided adequate evidence of long-term effectiveness of any pain medication, which incites an avenue for advancement of novel therapies. If efficacious, a discovery of a mechanism-based, highly selective compound would potentially serve as a non-addictive, superior analgesic agent to influence practice.