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（由适用提供）：生长抑制素是最初发现的神经肽，以抑制垂体的生长骑马分泌。生长抑素的作用是由名为SST1-5的五个相关G蛋白受体（GPCR）亚型介导的。通常，这种信号传导导致抑制骑马分泌和神经元活性。自发现以来，已经描述了生长抑素的许多作用，其特定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通路：包括外周神经末端，DRG神经元，脊髓的背角，脊髓中间神经元。尽管临床数据受到限制，但两项研究表明肽SST2激动剂奥曲肽的外围给药可降低晚期胃肠道癌患者的疼痛强度，并减少腹部手术患者阿片类药物的需求。选择性SST2和SST4激动剂在传统的啮齿动物疼痛模型中均有效。慢性疼痛仍然是高未满足医疗需求的重要领域，这不可能对患者及其护理人员造成巨大的烧伤。在美国，欧洲和许多其他国家，慢性疼痛的流行率高达人口五分之一，神经性疼痛的患病率估计为7-10％。神经性疼痛疾病，例如治疗后神经瘤（PHN）和疼痛的糖尿病神经病（PDN），由于缺乏有效性和/或剂量限制副作用，诸如抗癫痫病和抗抑郁剂等当前治疗方法无法缓解。作为我们SBIR资助的努力，发现SST2激动剂用于治疗垂体GH分泌腺瘤的腺瘤，引起了肢端肥大症，我们还发现了有效的，类似药物的小分子SST4激动剂以及SST4/2的双向动力学家。在此快速应用的I阶段部分中，这些化合物中的三种（所有潜在的SST4激动剂具有不同水平的SST2活性）将在创新的大鼠MODL中进行急性效率研究中，以更好地模拟PDN和PHN，以提供目标受体特异性。这将用于指导药物化学努力，以鉴定II期的其他潜在客户，最佳化合物进展为慢性疼痛模型的测试模型和初始毒理学研究，以根据每个初步的治疗窗口选择IND发育候选者。如果成功的话，该项目将导致选择候选药物以促进毒理学研究以支持首次人类研究。最终，将在后期临床试验中评估该分子，作为治疗后肝后神经蛋白酶（PHN）和疼痛糖尿病神经病（PDN）的潜在一类治疗，并有可能以其他形式的神经性疼痛进行评估。