Preclinical assessment of a novel systemic drug candidate for osteoarthritic pain

治疗骨关节炎疼痛的新型全身候选药物的临床前评估

• 批准号: 10642544
• 负责人: DENIS EVSEENKO
• 金额: $ 134.85万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642544
• 关键词: Ablation; Adult; Affect; Affective; Age; Aging; American; Analgesics; Animal Model; Animals; Ankle; Applications Grants; Arthralgia; Attenuated; Behavior; Behavioral Assay; Biological Availability; Bypass; Cartilage; Cavia; Chemicals; Chronic; Chronic inflammatory pain; Clinical; Conduct Clinical Trials; Control Animal; Custom; Data; Degenerative polyarthritis; Dependence; Development; Dimensions; Disease; Drug Kinetics; Effectiveness; Excretory function; Female; Fentanyl; Food; Frequencies; Freund' s Adjuvant; Guidelines; Human; IL6ST gene; Inflammation; Inflammatory; Injury; Interleukin-6; Joints; Knee; Life; MAP Kinase Gene; Mediating; Metabolism; Modeling; Modern Medicine; Molecular; Mus; Negative Reinforcements; Opioid; Oral; Outcome; Outcome Measure; Output; Oxycodone; Pain; Pain management; Pathogenesis; Pathologic; Pathway interactions; Patients; Peptide Initiation Factors; Pharmaceutical Preparations; Pharmacotherapy; Phenocopy; Pilot Projects; Plasma; Progressive Disease; Public Health; Quality of life; Rattus; Recommendation; Reporting; Resistance; Rewards; Role; Route; Sensory; Signal Transduction; Swelling; Symptoms; Syndrome; Technology; Testing; Therapeutic Agents; Time; Toxic effect; Trauma; Traumatic Arthropathy; Water; Woman; absorption; aged; analog; arm; articular cartilage; canine model; cartilage degradation; chronic pain; clinically relevant; cohort; conditioned place preference; cytokine; design; drug candidate; efficacy evaluation; efficacy testing; functional disability; glycoprotein 130; guinea pig model; inflammatory pain; intraperitoneal; joint destruction; joint inflammation; liquid chromatography mass spectrometry; male; men; multidisciplinary; new therapeutic target; novel; novel therapeutics; osteoarthritis pain; pain reduction; pain relief; pharmacologic; pre-clinical; pre-clinical assessment; prescription opioid; receptor; regenerative; response; scaffold; side effect; small molecule

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.

摘要 骨关节炎（OA），也称为退行性关节病，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大衰弱疾病，也是最紧迫的疾病之一。 当前公共卫生问题。OA最显著的临床症状是慢性关节疼痛， 发病时间会随着时间的推移而变化。疼痛相关的功能障碍的特点是干扰 日常活动的许多方面显著降低生活质量。尽管保留争议 由于依赖性、滥用、耐受性和毒性问题，阿片类药物是 当其他疼痛管理选项失败时，经常开处方用于疼痛控制。负 阿片类药物的后果表明有必要为OA疼痛管理提供替代途径。OA是一个 多因素疾病，涉及低度慢性炎症，部分由白细胞介素介导， 6/糖蛋白130（IL-6/gp 130）级联反应，导致基质逐渐降解和不可逆的破坏。 关节软骨最近的研究已经报道IL-6/gp 130信号转导参与了 炎症性病理性疼痛以前，我们已经证明，操纵细胞内残基， 在GP 130受体及其环境特异性下游信号传导中 该轴的促炎后果，同时促进有益的结果。我们的小组已经确定了一个 gp 130内的信号传导残基（Y814），其代表负责激活高表达的 gp 130的有害臂和小鼠中Y814的组成性消融抑制损伤诱导的OA的发展。 为了操纵gp 130下游的破坏性输出，包括那些由Y814调节的输出，我们 合成了一类能够选择性灭活gp 130信号传导的新的小分子化合物， 从而保护膝关节软骨免受基质降解并减轻大鼠和犬的疼痛 创伤后OA模型。通过多轮优化，我们命名为R159的类似物具有 显示出对gp 130 Y814的最有效和选择性抑制以及优异的吸收，分布， 代谢和排泄（ADME）特征。目前的拨款申请旨在系统地调查 gp 130 Y814在OA发病机制中的意义，并询问是否有针对性地 残留物将减弱OA相关的慢性疼痛。为此，我们将首先定义全身药代动力学 大鼠口服和腹膜内给药后R159的参数。随后，我们将确定 全身施用R159在减轻疼痛和功能性和情感行为中的功效 临床CFA诱导的踝关节OA大鼠和全身OA豚鼠模型。迄今为止未进行临床试验 已经提供了足够的证据证明任何止痛药的长期有效性， 来推动新疗法的发展如果有效的话，一种基于机制的，高选择性的化合物的发现 将潜在地用作非成瘾性的、上级镇痛剂以影响实践。