Novel Glycosylated Delta Opioid Receptor Agonists for Chronic Inflammatory Pain

新型糖基化 Delta 阿片受体激动剂治疗慢性炎症疼痛

• 批准号: 8246995
• 负责人: Mark S Kleven
• 金额: $ 46.88万
• 依托单位: BIOUSIAN BIOSYSTEMS, INC. (BBI)
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8246995
• 关键词: Acute; Acute inflammatory pain; Adverse effects; Affinity; Agonist; Analgesics; Applications Grants; Award; Binding; Biological Assay; Biological Availability; Blood; Blood specimen; Brain; Budgets; Cardiac; Characteristics; Chronic inflammatory pain; Clinical Trials; Collaborations; Complement; Cytochrome P450; Databases; Dependence; Development; Diagnostic; Dose; Drug Delivery Systems; Drug Formulations; Drug Interactions; Drug usage; Employee; Erythrocytes; Funding; Glycopeptides; Goals; Grant; Harvest; Human; Hydrocodone; In Vitro; Inhibitory Concentration 50; Lead; Letters; Libraries; Ligation; Measures; Methods; Modeling; Molecular; Morphine; Nerve Tissue; Nociception; Opioid; Opioid Analgesics; Opioid Receptor; Oral; Oxycodone; Pain; Parents; Peptides; Peripheral Nervous System; Pharmaceutical Preparations; Pharmacology; Phase; Pilot Projects; Plasma Proteins; Property; Protein Binding; Rattus; Reaction Time; Relative (related person); Research; Respiration; Risk; Rodent Model; Route; Running; Safety; Sedation procedure; Series; Small Business Innovation Research Grant; Spinal nerve structure; Stomach; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Index; Time; Toxicology; addiction; base; carcinogenicity; cell motility; chronic pain; commercialization; delta opioid receptor; deltorphin; drug development; gabapentin; glycosylation; improved; in vivo; in vivo Model; kappa opioid receptors; liquid chromatography mass spectrometry; meetings; mu opioid receptors; novel; painful neuropathy; pre-clinical; programs; public health relevance; receptor; research and development; sciatic nerve

DESCRIPTION (provided by applicant): Traditionally, Mu opioid receptor (MOR) agonists have not been given as first line treatments for neuropathic pain due to their significant adverse side effects. Biousian Biosystems Inc, (BBI) is developing novel glycosylated peptide-based delta opioid receptor (DOR) targeted drugs for the treatment of chronic pain. Preclinical profiles for DOR agonists indicate broad-spectrum analgesic efficacy with greatly reduced side effects compared to the currently used MOR opioid analgesics. The glycosylation of DOR selective peptides also represents a BBI platform technology that improves stability and enhances other PK characteristics of the parent peptide including oral and CNS bioavailability, issues that have impeded the development of peptide- based therapeutics. A successful glycopeptide drug would represent a novel, first in class therapeutic agent with significant advantages, thereby transforming the development of peptide, as well as pain therapeutics. BBI successfully completed its phase I SBIR grant, meeting or exceeding all milestones within the specific aims, and doing so on time and within budget. This included the synthesis of a library of glycosylated deltorphin-based peptides that possess predicted selectivity and efficacy for the delta opioid receptor (DOR). More specifically, a lead candidate emerged (BBI 11008) and backups were identified. These compounds have high affinity (low nM) and functional potency in vitro, and are at least 1000x functionally selective for DOR over MOR and kappa opioid receptors (KOR). Select compounds were advanced into in vivo antinociceptive studies, and demonstrated excellent efficacy in acute thermal nociceptive and sub-acute inflammatory pain models. Additional studies were performed in parallel with Phase I funded R&D efforts in order to begin assessment of safety/side-effect profiles and oral formulation/bioavailability. This phase II SBIR application is a logical extension of the R&D successfully completed in the company's Phase I award. The proposed studies will further advance the pharmacology of a lead compound (BBI 11008) through a development tract that, if successful, will culminate in a successful IND filing. This will be achieved in Specific Aim 1a by determining and critically evaluating the DMPK properties of BBI 11008 and in Specific Aim 1b by identifying potential safety risks of the lead candidate BBI 11008. In Specific Aim 2, we will assess the potency and efficacy of BBI 11008 in the rat spinal nerve ligation (SNL) model of neuropathic pain. Finally, in Specific Aim 3, the relative side effect advantage of BBI 11008 will be determined compared to drugs used in neuropathic pain. BBI 11008 will be assessed in in-vivo models of respiration, abuse potential, tolerance/dependence and gastric motility and compared to side effects typically associated with traditional MOR agonists, e.g. morphine and/or gabapentin, a drug commonly prescribed for neuropathic pain. The research is complemented by a commercialization plan and the drug development expertise of BBI employees, advisors and collaborators as documented in the grant application, biosketches and support letters. PUBLIC HEALTH RELEVANCE: Traditionally, Mu opioid agonists have not been given as a first line treatment for neuropathic pain due to their significant adverse side effects. Biousian Biosystems, Inc (BBI) is developing novel glycosylated peptide-based, delta opioid receptor-targeted drugs to treat chronic pain with improved efficacy and without the significant side effects of currently used opioid analgesics. BBI plans to continue a successful Phase I program with studies that will further advance the pharmacology of a lead compound (BBI 11008) through a development tract that, if successful, will culminate in a successful IND filing.

描述（由申请人提供）：传统上，Mu阿片受体（MOR）激动剂由于其显着的不良副作用而未被用作神经性疼痛的一线治疗。 Biousian Biosystems Inc, (BBI) 正在开发新型基于糖基化肽的 δ 阿片受体 (DOR) 靶向药物，用于治疗慢性疼痛。 DOR 激动剂的临床前概况表明，与目前使用的 MOR 阿片类镇痛药相比，DOR 激动剂具有广谱镇痛功效，且副作用大大减少。 DOR 选择性肽的糖基化也代表了一种 BBI 平台技术，可提高稳定性并增强母体肽的其他 PK 特性，包括口服和 CNS 生物利用度，这些问题阻碍了基于肽的疗法的开发。成功的糖肽药物将代表一种新型的、一流的治疗剂，具有显着的优势，从而改变肽以及疼痛治疗的发展。 BBI 成功完成了第一阶段 SBIR 拨款，达到或超过了特定目标内的所有里程碑，并且在预算范围内按时完成。这包括合成一个基于糖基化德尔托啡的肽库，该肽库对 δ 阿片受体 (DOR) 具有预测的选择性和功效。更具体地说，出现了主要候选者（BBI 11008）并确定了备份。这些化合物在体外具有高亲和力（低 nM）和功能效力，并且对 DOR 的功能选择性比 MOR 和 kappa 阿片受体 (KOR) 至少高 1000 倍。选择的化合物已进入体内抗伤害研究，并在急性热伤害和亚急性炎症疼痛模型中表现出优异的功效。与第一阶段资助的研发工作同时进行了其他研究，以便开始评估安全性/副作用特征和口服制剂/生物利用度。该第二阶段 SBIR 申请是公司第一阶段奖项中成功完成的研发的合理延伸。拟议的研究将通过开发途径进一步推进先导化合物（BBI 11008）的药理学，如果成功，最终将成功提交 IND 申请。这将在具体目标 1a 中通过确定和严格评估 BBI 11008 的 DMPK 特性来实现，在具体目标 1b 中通过识别主要候选 BBI 11008 的潜在安全风险来实现。在具体目标 2 中，我们将评估 BBI 11008 在大鼠脊髓神经结扎 (SNL) 神经性疼痛模型中的效力和功效。最后，在具体目标 3 中，将确定 BBI 11008 与用于神经性疼痛的药物相比的相对副作用优势。 BBI 11008 将在呼吸、滥用潜力、耐受性/依赖性和胃动力的体内模型中进行评估，并与通常与传统 MOR 激动剂相关的副作用进行比较，例如吗啡和/或加巴喷丁，一种通常用于治疗神经性疼痛的药物。该研究得到商业化计划以及 BBI 员工、顾问和合作者的药物开发专业知识的补充，如拨款申请、生物草图和支持信中所述。 公众健康相关性：传统上，Mu 阿片类激动剂由于其明显的不良副作用而未作为神经性疼痛的一线治疗药物。 Biousian Biosystems, Inc (BBI) 正在开发新型基于糖基化肽的 δ 阿片受体靶向药物，用于治疗慢性疼痛，提高疗效，并且没有目前使用的阿片类镇痛药的显着副作用。 BBI 计划继续成功开展第一阶段计划，通过研究进一步推进先导化合物 (BBI 11008) 的药理学，如果成功，最终将成功提交 IND 申请。