Small molecule somatostatin agonists for neuropathic pain

 描述（由申请方提供）：生长抑素是最初发现的抑制垂体生长激素分泌的神经肽。生长抑素的作用是由五个相关的G蛋白受体（GPCR）亚型命名为sst 1 -5介导的。一般来说，这种信号传导导致激素分泌和神经元活性的抑制。自发现以来，生长抑素的许多作用已被描述为具有依赖于所涉及的受体亚型和其表达的细胞类型的特异性作用。例如，生长抑素活性通过在多个位点表达的sst 2和sst 4受体亚型抑制伤害性信号传导途径：包括外周神经末梢、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，外周给予肽sst 2激动剂奥曲肽可减轻晚期胃肠道癌患者的疼痛强度，并减少腹部手术患者对阿片类药物的需求。选择性SST 2和SST 4激动剂在传统啮齿动物疼痛模型中均有效。慢性疼痛仍然是高度未满足的医疗需求的一个重要领域，给患者及其护理人员带来了巨大的负担。在美国、欧洲和许多其他国家，慢性疼痛的患病率高达人口的五分之一，神经性疼痛的患病率估计为7- 10%。神经性疼痛病症，例如疱疹后神经痛（PHN）和疼痛性糖尿病性神经病变（PDN），特别是由于缺乏功效和/或剂量限制性副作用，目前的治疗例如抗癫痫药和抗抑郁药难以缓解。作为我们SBIR资助的发现用于治疗引起肢端肥大症的垂体GH分泌腺瘤的sst 2激动剂的努力的一部分，我们还发现了有效的药物样小分子sst 4激动剂以及sst 4/2双重激动剂。在该快速通道申请的I期部分中，这些化合物中的三种（所有具有不同水平的sst 2活性的强效sst 4激动剂）将在更好地模拟PDN和PHN以提供靶受体特异性谱的创新大鼠模型中的急性功效研究中进行分析。这将用于指导药物化学工作，以确定II期的其他先导化合物，最佳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，以根据每个初步治疗窗口选择IND开发候选药物。如果成功，该项目将为IND前毒理学研究选择候选药物，以支持首次人体研究。最终，这种分子将在后期临床试验中作为疱疹后神经痛（PHN）和疼痛性糖尿病神经病变（PDN）的潜在一流治疗进行评估，并有可能在其他形式的神经性疼痛中进行评估。

 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.