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

描述(申请人提供)：治疗各种原因的外周疼痛仍然是一个主要的未得到满足的医疗需求，在一生中的某个时候影响到全国数千万到数亿人。Kappa-阿片激动剂在外周疼痛模型中被证明特别有效，但受到中枢调节效应的影响，限制了它们的发展。也许最有希望开发的kappa激动剂是CR665，它是四肽D-Phe-D-Phe-D-NLE-D-Arg-NH2的衍生物，静脉注射时表现出高(但不是绝对)的外周到中枢(CNS)选择性。临床研究表明，对内脏和神经病理性疼痛的患者有显著好处；然而，口服该化合物并不有效，这大大限制了其作为外周疼痛止痛剂的潜在用途。作为概念的证明，将Halimed PharmPharmticals非天然氨基酸技术应用于CR665产生的衍生物在啮齿动物醋酸诱导的周围疼痛扭体试验中显示出口腔活性。因此，我们， 假设将卤化多肽修饰技术应用于D-Phe-D-Phe-D-NLE-D-Arg-NH2将导致口服外周kappa阿片受体激动剂，该激动剂可作为药物实体开发。为了评估这一假设，我们将完成三个具体目标。具体目标1是确定潜在的潜在候选人。D-Phe-D-Phe-D-NLe-D-Arg-NH2的三个残基将用Halimed矩阵方法依次修饰以产生铅：第一，D-Arg(4)侧链，第二，n-Leu(3)侧链，第三，-(C=O)NH2的C-末端。每种化合物都将在扭动模型中进行评估。在每一次筛选后，确定的最佳残留物(S)然后可以并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”。将对从具体目标1出现的至少两种化合物的特性进行评估，以进一步将它们定义为适当的线索，其中将包括确定EC50、外周和中枢效力比率，以及对kappa-over-u-和Delta-阿片受体的选择性已经确定了每次评估的最低基准值。具体目标3是评估其他潜在的阿片类药物副作用，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个潜在铅的最大耐受量并评估耐受性发展的潜力来启动。完成这些特定目标将确定具有良好特征的、经过审查的线索，以证明进入正式的临床前阶段是合理的 该项目第二阶段的发展。这项第一阶段的工作将在Halimed制药公司进行，并与PI的长期合作者南卡罗来纳医科大学的Craig Beeson博士合作进行。

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.