Small molecule somatostatin agonists for neuropathic pain

小分子生长抑素激动剂治疗神经性疼痛

• 批准号: 8903624
• 负责人: RICHARD SCOTT STRUTHERS
• 金额: $ 32.61万
• 依托单位: CRINETICS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8903624
• 关键词: Abdomen; Absence of pain sensation; Acromegaly; Acute; Adverse effects; Agonist; Antiepileptic Agents; Area; Capsaicin; Caregivers; Chemicals; Chronic; Clinical Data; Clinical Research; Clinical Trials; Country; Cytochrome P450; Development; Diabetic Neuralgia; Dose-Limiting; Europe; Evaluation; Formalin; Funding; GTP-Binding Proteins; Health; Hormones; Human; Interneurons; Lead; Liver; Malignant neoplasm of gastrointestinal tract; Maximum Tolerated Dose; Mediating; Medical; Metabolic; Modeling; Names; Neurons; Neuropeptides; Nociception; Octreotide; Operative Surgical Procedures; Opioid; Pain; Pain intensity; Patients; Peptides; Peripheral; Peripheral Nerves; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Pituitary Gland; Population; Postherpetic neuralgia; Preparation; Prevalence; Property; Rattus; Rodent; Rodent Model; Role; Safety; Signal Pathway; Signal Transduction; Site; Small Business Innovation Research Grant; Solubility; Somatostatin; Somatostatin Receptor; Somatotropin; Specificity; Spinal; Spinal cord posterior horn; Staging; Syndrome; Tachyphylaxis; Testing; Therapeutic; Toxicology; Work; adenoma; base; candidate selection; cell type; central sensitization; chemical stability; chronic pain; drug candidate; efficacy testing; innovation; novel; painful neuropathy; receptor; small molecule; somatostatin receptor 4

 DESCRIPTION (provided by applicant): Somatostatins are neuropeptides originally discovered to inhibit growth hormone secretion by the pituitary. The actions of somatostatins are mediated by five related G protein receptor (GPCR) subtypes named sst1-5. In general, this signaling results in inhibition of hormone secretion and neuronal activity. Since their discovery, many roles of somatostatin have been described with specific effects dependent upon the receptor subtype involved and the cell type in which it is expressed. For example, somatostatin activity inhibits nociceptive signaling pathways via sst2 and sst4 receptor subtypes that are expressed at multiple sites: including peripheral nerve terminals, DRG neurons, the dorsal horn of the spinal cord, and spinal interneurons. Although clinical data is limited, two studies indicat the peripheral administration of the peptide sst2 agonist octreotide reduces pain intensity in patients with advanced gastrointestinal cancer and reduces the need for opioids in abdominal surgery patients. Both selective sst2 and sst4 agonists are effective in traditional rodent pain models. Chronic pain remains an important area of high unmet medical need that imposes an enormous burden on patients and their caregivers. In the US, Europe, and many other countries the prevalence of chronic pain is as high as one-fifth the population, with the prevalence of neuropathic pain estimated at 7-10%. Neuropathic pain conditions such as post-herpetic neuralgia (PHN) and painful diabetic neuropathy (PDN) in particular are poorly relieved by current treatments such as anti-epileptics and anti-depressants due to a lack of efficacy and/or dose-limiting side effects. As part of our SBIR-funded effort to discover sst2 agonists for the treatment of pituitary GH-secreting adenomas that cause acromegaly, we have also discovered potent, drug-like small molecule sst4 agonists as well as sst4/2 dual-agonists. In the Phase I portion of this Fast Track application, three of these compounds (all potent sst4 agonists with differing levels of sst2 activity) will be profiled in acute efficacy studies in innovative rat modls that better mimic PDN and PHN to provide a target receptor specificity profile. This will be used to guide medicinal chemistry efforts to identify additional Leads in Phase II, with the best compounds advancing to testing models of chronic pain models and initial toxicology studies to select an IND Development Candidate based on the preliminary therapeutic window for each. If successful, this project will result in the selection of a drug candidate for pre-IND enabling toxicology studies to support first-in-human studies. Ultimately, this molecule would be evaluated in later stage clinical trials as a potential First-In-Class treatment for post-herpetic neuralgia (PHN) and painful diabetic neuropathy (PDN), with the potential to be evaluated in other forms of neuropathic pain.

 描述（由申请人提供）：生长抑素是最初被发现抑制垂体分泌生长激素的神经肽。生长抑素的作用由名为 sst1-5 的五种相关 G 蛋白受体 (GPCR) 亚型介导。一般来说，这种信号传导会抑制激素分泌和神经元活动。自发现以来，生长抑素的许多作用已被描述，其具体作用取决于所涉及的受体亚型及其表达的细胞类型。例如，生长抑素活性通过在多个部位表达的 sst2 和 sst4 受体亚型抑制伤害性信号传导途径：包括周围神经末梢、DRG 神经元、脊髓背角和脊髓中间神经元。尽管临床数据有限，但两项研究表明外周给药肽 sst2 激动剂奥曲肽可降低晚期胃肠癌患者的疼痛强度，并减少腹部手术患者对阿片类药物的需求。选择性 sst2 和 sst4 激动剂在传统啮齿动物疼痛模型中均有效。慢性疼痛仍然是医疗需求未得到满足的一个重要领域，给患者及其护理人员带来巨大负担。在美国、欧洲和许多其他国家，慢性疼痛的患病率高达五分之一的人口，其中神经性疼痛的患病率估计为 7-10%。由于缺乏疗效和/或剂量限制性副作用，目前的治疗方法（例如抗癫痫药和抗抑郁药）对带状疱疹后神经痛（PHN）和疼痛性糖尿病神经病（PDN）等神经性疼痛的缓解效果不佳。作为 SBIR 资助的研究的一部分，我们致力于发现 sst2 激动剂来治疗导致肢端肥大症的垂体 GH 分泌腺瘤，我们还发现了有效的药物样小分子 sst4 激动剂以及 sst4/2 双激动剂。在该快速通道申请的第一阶段部分，其中三种化合物（都是具有不同水平 sst2 活性的强效 sst4 激动剂）将在创新大鼠模型中进行急性功效研究，这些模型可以更好地模拟 PDN 和 PHN，以提供目标受体特异性特征。这将用于指导药物化学工作，以确定第二阶段的其他先导化合物，最好的化合物将进入慢性疼痛模型的测试模型和初步毒理学研究，以根据每种化合物的初步治疗窗口选择 IND 开发候选药物。如果成功，该项目将为 IND 前的毒理学研究选择候选药物，以支持首次人体研究。最终，该分子将在后期临床试验中作为带状疱疹后神经痛（PHN）和疼痛性糖尿病神经病（PDN）的潜在一流治疗药物进行评估，并有可能在其他形式的神经性疼痛中进行评估。