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.

抽象的 骨关节炎（OA），也称为退化性关节疾病，是一种进行性疾病，最终导致 功能性残疾，使其成为全球第11位最令人衰弱的疾病，也是最大的紧迫性疾病之一 当前的公共卫生问题。 OA的最显着临床症状是慢性关节疼痛逐渐 发病随着时间的流逝而恶化。与疼痛相关的功能障碍的特征是干扰 日常活动的许多方面大大降低了生活质量。尽管有争议 由于依赖性，滥用，耐受性和毒性问题，当前指南的建议，阿片类药物是 当其他疼痛管理选择失败时，经常处方用于疼痛。负 阿片类药物的后果证明了OA疼痛管理的替代路线选择的必要性。 OA是一个 多因素疾病涉及低度，慢性炎症，部分是由白介素介导的 6/糖蛋白130（IL-6/gp130）级联导致逐渐矩阵降解和不可逆转的破坏 关节软骨。最近的研究报告说，IL-6/GP130信号传导与 炎症，病理疼痛。以前，我们已经证明了对细胞内残基的操纵 在GP130受体及其上下文中，特定于下游信号可以被解构以选择性绕过 该轴的促炎后果，同时促进有益结果。我们的小组已经确定了 GP130内的信号传导残基（Y814）代表了负责激活高度激活的启动因子 GP130的有害部门和小鼠Y814的本构消融抑制了损伤引起的OA的发展。 为了操纵GP130下游的破坏性输出，包括Y814管制的输出，我们有 合成了一类新的小分子化合物，能够选择性地灭活GP130信号和 因此，保护​​膝盖的关节软骨免受基质降解的侵害，并减轻大鼠和犬的疼痛 创伤后OA的模型。通过多发优化，我们称为R159的模拟 显示了GP130Y814的最有效和选择性抑制以及出色的吸收，分布， 代谢和排泄物（ADME）。当前的赠款应用程序旨在系统地调查 GP130Y814在OA的发病机理中的意义，并询问药理学是否针对这一点 残留物将减轻与OA相关的慢性疼痛。为此，我们将首先定义系统的药代动力学 口服和腹膜内给予大鼠后R159的参数。随后，我们将确定 系统施用的R159在缓解疼痛和功能和情感行为方面的功效 临床CFA诱导的脚踝OA大鼠和广义的OA豚鼠模型。迄今未进行临床试验 已经提供了任何止痛药的长期有效性的足够证据，这促使途径 为了进步新型疗法。如果有效，则发现基于机制的高度选择性化合物 可能会成为一种影响实践的非副词，上级镇痛药。