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: 8057505
• 负责人: Mark S Kleven
• 金额: $ 51.42万
• 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 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8057505
• 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; 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（莫尔）激动剂由于其显著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激动剂的临床前特征表明，与目前使用的莫尔阿片类镇痛剂相比，具有广谱镇痛功效，副作用大大降低。DOR选择性肽的糖基化也代表了BBI平台技术，其改善了稳定性并增强了母体肽的其他PK特征，包括口服和CNS生物利用度，这些问题阻碍了基于肽的治疗剂的开发。一个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，从而改变肽的发展，以及疼痛治疗。BBI成功地完成了第一阶段SBIR赠款，达到或超过了具体目标内的所有里程碑，并在预算范围内按时完成。这包括合成基于糖基化deltorphin的肽的文库，所述肽对δ阿片受体（DOR）具有预测的选择性和功效。更具体地说，出现了一个主要候选人（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的功能选择性是对莫尔和κ阿片受体（KOR）的至少1000倍。选择的化合物被推进到体内抗伤害性研究中，并且在急性热伤害性和亚急性炎性疼痛模型中表现出优异的功效。与I期资助的研发工作平行进行了其他研究，以便开始评估安全性/副作用特征和口服制剂/生物利用度。这第二阶段SBIR应用程序是一个合理的延伸研发成功完成了该公司的第一阶段奖。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，将最终成功提交IND申请。这将在具体目标1a中通过确定和严格评价BBI 11008的DMPK特性来实现，在具体目标1b中通过识别主要候选药物BBI 11008的潜在安全性风险来实现。在具体目标2中，我们将评估BBI 11008在神经性疼痛的大鼠脊神经结扎（SNL）模型中的效力和疗效。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。将在呼吸、滥用可能性、耐受性/依赖性和胃动力的体内模型中评估BBI 11008，并将其与通常与传统莫尔激动剂相关的副作用进行比较，例如吗啡和/或加巴喷丁，一种通常用于神经性疼痛的药物。该研究得到了商业化计划和BBI员工，顾问和合作者的药物开发专业知识的补充，如赠款申请，bisketches和支持信中所记录的。 公共卫生关系：传统上，Mu阿片激动剂由于其显著的不良副作用而未作为神经性疼痛的一线治疗给予。Biousian Biosystems，Inc（BBI）正在开发新型糖基化肽，δ阿片受体靶向药物，以治疗慢性疼痛，提高疗效，并且没有目前使用的阿片类镇痛药的显著副作用。BBI计划继续一个成功的I期项目，通过一个开发区域进一步推进先导化合物（BBI 11008）的药理学研究，如果成功的话，将最终成功提交IND申请。