Peptide-Derived Orally-Active Kappa-Opioid Receptor Agonists for Peripheral Pain

描述（由申请人提供）：各种起源的外周疼痛的治疗仍然是一个主要的未满足的医疗需求，影响了全国数千万至数亿人在他们一生中的某个时候。κ-阿片样物质激动剂已在外周疼痛模型中显示出特别有效，但遭受中枢介导的作用，这限制了它们的发展。也许正在开发的最有前途的κ激动剂是CR 665，它是四肽D-Phe-D-Phe-D-Nle-D-Arg-NH 2的衍生物，当IV给药时，它表现出高（但不是绝对的）外周到中枢（CNS）的选择性。临床研究已显示在内脏和神经性疼痛患者中的显著益处;然而，该化合物在口服给药时没有活性，这显著限制了其作为外周疼痛镇痛剂的潜在用途。作为概念证明，将Halimed Pharmaceuticals非天然氨基酸技术应用于CR 665产生的衍生物在啮齿动物乙酸诱导的外周疼痛扭体试验中表现出口服活性。因此， 假设将Halimed肽修饰技术应用于D-Phe-D-Phe-D-Nle-D-Arg-NH 2将产生可口服外周κ阿片样受体激动剂，其可被开发为药物实体。为了评估这个假设，我们将完成三个具体目标。具体目标1是识别潜在的领导候选人。D-Phe-D-Phe-D-Nle-D-Arg-NH 2的三个残基将使用Halimed矩阵方法依次修饰以产生前导：第一，D-Arg（4）侧链，第二，n-leu（3）侧链，第三，-（C=O）NH 2 C-末端。将在扭体模型中评价每种化合物。每次筛选后，可将鉴定的最佳残留物掺入用于后续筛选的化合物中。具体目标2是从“命中”中确定“线索”。将评价特异性目标1中出现的至少两种化合物的特征，以进一步将其定义为适当的先导化合物，这将包括测定EC 50、外周与CNS效价比以及κ阿片受体相对于μ阿片受体和δ阿片受体的选择性，已定义了每次评价的最小基准值。具体目标3是评价其他潜在阿片类药物副作用，包括烦躁不安、镇静、肠梗阻、呼吸抑制、成瘾/依赖和利尿。毒理学筛选将通过确定每种潜在电极导线的最大耐受剂量并评价耐受性发展的可能性来启动。完成这些特定目标将识别出充分表征的、经过审查的电极导线，以证明进入正式临床前研究的合理性 在这个项目的第二阶段。本I期研究将在Halimed Pharmaceuticals进行，并与PI的长期合作者南卡罗来纳州医科大学的克雷格比森博士合作。

DESCRIPTION (provided by applicant): Treatment of peripheral pain of various origins remains a major unmet medical need, affecting tens to hundreds of millions of people nationwide at some time during their lives. Kappa-opioid agonists have been shown in peripheral pain models to be particularly efficacious but suffer from centrally mediated effects that have limited their development. Perhaps the most promising kappa-agonist under development is CR665, a derivative of the tetrapeptide D-Phe-D-Phe-D-Nle-D-Arg-NH2, which exhibits high (but not absolute) peripheral to central (CNS) selectivity when administered IV. Clinical studies have shown significant benefit in patients with visceral and neuropathic pain; however, the compound is not active when administered orally which significantly limits its potential use as an analgesic for peripheral pain. As proof of concept, application of the Halimed Pharmaceuticals non-natural amino acid technology to CR665 produced derivatives that exhibit oral activity in the rodent acetic acid- induced writhing assay for peripheral pain. We, therefore, hypothesize that application of the Halimed peptide modification technology to D-Phe-D-Phe-D-Nle-D-Arg-NH2 will result in an orally available peripheral kappa opioid receptor agonist that can be developed as a pharmaceutical entity. To evaluate this hypothesis, we will complete three Specific Aims. Specific Aim 1 is identification of potential lead candidates. Three residues of D-Phe-D-Phe-D-Nle-D-Arg-NH2 will be modified in turn using the Halimed matrix approach to lead generation: first, the D-Arg(4) side-chain, second, the n-leu(3) side chain, third, the -(C=O)NH2 C-terminus. Each compound will be evaluated in the writhing model. After each screen, the best residue(s) identified can then be incorporated into compounds used for the subsequent screens. Specific Aim 2 is determination of "leads" from "hits". At least two compounds emerging from Specific Aim 1 will be evaluated for characteristics to further define them as appropriate leads, which will include determination of EC50s, the peripheral to CNS potency ratios, and selectivity for the kappa- over the mu- and delta-opioid receptors Minimal benchmark values for each evaluation have been defined. Specific Aim 3 is evaluation of other potential opioid side effects, including dysphoria, sedation, ileus, respiratory depression, addiction/dependence and diuresis. Toxicology screening will be initiated by determining the maximal tolerated dose for each potential lead and evaluating the potential for tolerance development. Completion of these Specific Aims will identify well-Characterized, vetted leads to justify entering formal preclinical development in Phase II of this project. This Phase I effort will be performed at Halimed Pharmaceuticals and in collaboration with the PI's long-term collaborator, Dr. Craig Beeson at the Medical University of South Carolina.