Novel Glycosylated Delta Opioid Receptor Agonists for Chronic Inflammatory Pain

描述(由申请人提供)：传统上，Mu阿片受体(MOR)激动剂由于其显著的副作用而没有被作为神经性疼痛的一线治疗药物。Biousian BiosSystems Inc.(BBI)正在开发基于糖基化多肽的增量阿片受体(DOR)靶向药物，用于治疗慢性疼痛。DOR激动剂的临床前资料显示，与目前使用的MOR阿片类止痛药相比，DOR激动剂的广谱止痛效果和副作用大大减少。DOR选择性多肽的糖基化也代表了一种BBI平台技术，它提高了稳定性，并增强了母肽的其他PK特性，包括口服和中枢神经系统的生物利用度，这些问题阻碍了基于多肽的疗法的发展。一种成功的糖肽药物将代表着一种新的、一流的治疗药物，具有显著的优势，从而改变肽以及疼痛治疗的发展。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，并按时并在预算内做到了这一点。这包括合成一个基于Deltorphin的糖基化多肽文库，这些多肽对Delta阿片受体(DOR)具有预期的选择性和有效性。更具体地说，出现了一个领先的候选者(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，对DOR的功能选择性至少是MOR和kappa阿片受体(KOR)的1000倍。选定的化合物进入体内抗伤害性研究，并在急性热伤害性和亚急性炎症性疼痛模型中显示出良好的效果。在第一阶段资助的研发工作的同时还进行了其他研究，以便开始评估安全性/副作用概况和口服制剂/生物利用度。这一第二阶段的SBIR应用是该公司第一阶段奖项中成功完成的研发的合乎逻辑的延伸。拟议的研究将通过开发区域进一步推进先导化合物(BBI 11008)的药理学，如果成功，最终将在IND申请成功。这将在具体目标1a中通过确定和批判性地评估BBI 11008的DMPK属性来实现，并在具体目标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神经病理性疼痛模型中的效力和疗效。最后，在具体目标3中，将确定与用于神经性疼痛的药物相比，BBI 11008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，并与传统MOR激动剂通常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病理性疼痛的药物。这项研究还得到了BBI员工、顾问和合作者的商业化计划和药物开发专业知识的补充，如赠款申请、生物素描和支持信中所述。 公共卫生相关性：传统上，Mu阿片类激动剂因其显著的副作用而不被作为神经病理性疼痛的一线治疗。Biousian BiosSystems，Inc.(BBI)正在开发基于糖基化多肽的、Delta阿片受体靶向的新型药物，用于治疗慢性疼痛，具有更高的疗效，并且没有目前使用的阿片类止痛药的显著副作用。BBI计划继续一项成功的第一阶段计划，研究将通过开发区域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。

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.