Nonpeptide, oral somatostatin agonists for congenital hyperinsulinemias

用于治疗先天性高胰岛素血症的非肽口服生长抑素激动剂

• 批准号: 9408384
• 负责人: Stephen F Betz
• 金额: $ 29.74万
• 依托单位: CRINETICS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2018-06-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9408384
• 关键词: Abbreviations; Acute; Adult; Adverse effects; Agonist; Alpha Cell; B-Lymphocytes; Bibliography; Blood Glucose; Cessation of life; Child; Chronic; Communities; Consanguinity; Cytochrome P450; D Cells; Defense Mechanisms; Development; Developmental Delay Disorders; Diabetes Mellitus; Diazoxide; Disease; Effectiveness; Endocrine System Diseases; Evaluation; Functional disorder; Genes; Glucagon; Glucose; Glyburide; Goals; Government; Growth; Hair; Hormonal; Human; Hyperinsulinism; Hypoglycemia; In Vitro; Incidence; Infant; Infusion procedures; Inherited; Injectable; Insulin; Islets of Langerhans; Label; Lead; Learning Disabilities; Life; Live Birth; Liver; Maximum Tolerated Dose; Medical; Metabolic; Modeling; Molecular Models; Mutation; Necrotizing Enterocolitis; Neurologic; Neuropeptides; Newborn Infant; No-Observed-Adverse-Effect Level; Octreotide; Operative Surgical Procedures; Oral; Oral Administration; Pancreas; Pancreatectomy; Pathogenesis; Pathway interactions; Patients; Peptides; Persistent Hyperinsulinemia Hypoglycemia of Infancy; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Pituitary Gland; Population; Preparation; Property; Rattus; Rest; Rodent Model; Safety; Seizures; Signal Transduction; Solubility; Somatostatin; Somatostatin Receptor; Somatotropin; Testing; Therapeutic; Toxicology; base; blood glucose regulation; design; diabetic; drug candidate; improved; inhibitor/antagonist; innovation; insulin secretion; islet; lead series; molecular modeling; neonate; novel therapeutics; peptide drug; prevent; programs; receptor; small molecule

Project Summary Hyperinsulinemic hypoglycemia (HH) is one of the most frequent causes of persistent hypoglycemia in infants and can result in seizures, developmental delays, learning disabilities, and even death. The most severe form of HH is inherited and referred to as congenital hyperinsulinism (CHI). CHI largely results from mutations in key genes in the insulin secretion pathway in the islets of Langerhans in the pancreas. Suspicion of CHI is confirmed by tests including the need to implement a high glucose infusion rate to maintain normal blood glucose levels. Currently, the only medical therapies used to treat CHI are used off-label. Typically, diazoxide (an insulin secretion inhibitor) is tried first, though it is often ineffective and has a side effect that causes abnormal and excessive hair growth over much of the body. The peptide sst receptor agonist octreotide is also used off-label for patients that are unresponsive to diazoxide or in conjunction with poor responders. Its pharmacological profile (sst2>sst5) leads to a host of unwanted side effects, including suppression of glucagon secretion which is detrimental to the CHI patient's utmost need, as well as inhibition of the growth hormone axis at the pituitary. Despite their poor profiles, these therapies are tried because the next line of treatment is typically a partial or full pancreatectomy. Even when successful, the result of this surgery is that the patient becomes diabetic and must actively manage glucose for the rest of their lives. Therefore, a significant unmet medical need exists for agents designed to specifically and effectively treat CHI. Here, we lay out our plan to develop orally-available, selective sst5-, sst3-, and/or dual sst5/3 agonists for the treatment of infants and children with CHI and other hyperinsulinemic disorders. Such a compound represents a major advance for infants with CHI and promises to provide specifically directed insulin control with the goal of preventing or delaying pancreatectomy without the excess of side effects that are carried along with current treatments.

项目摘要 高胰岛素低血糖（HH）是婴儿持续性低血糖的最常见原因之一 并可能导致癫痫发作，发展延误，学习障碍甚至死亡。最严重的形式 HH继承并称为先天性高胰岛素（CHI）。 CHI很大程度上是由密钥突变引起的 胰腺胰岛胰岛胰岛分泌途径中的基因。 怀疑CHI通过测试证实，包括实施高葡萄糖输注率以维持 正常血糖水平。目前，用于治疗CHI的唯一医疗疗法是在标签外使用的。通常， 首先尝试二氮二氧化物（一种胰岛素分泌抑制剂），尽管它通常无效，并且具有导致的副作用 在大部分身体上的异常和过度的头发生长。肽SST受体激动剂奥曲肽也是 用于对二氮氧化物无反应的患者或与较差的反应者一起使用的患者。它是 药理特征（SST2> SST5）导致许多不必要的副作用，包括抑制胰高血糖素 分泌不利于Chi患者的最大需求，以及对生长激素轴的抑制 在垂体。尽管概况差，但尝试了这些疗法，因为下一条治疗方法通常是 部分或完整的胰腺切除术。即使成功，此手术的结果是患者变得 糖尿病性，必须在余生中积极管理葡萄糖。因此，巨大的未满足的医疗需求 对于旨在专门有效地处理CHI的代理商而存在。 在这里，我们制定了计划开发口服可用的，选择性的SST5-，SST3-和/或双SST5/3激动剂的计划 治疗婴儿和其他高胰岛素疾病的儿童。这样的化合物代表 对于患有CHI的婴儿的重大进步，并承诺提供特定定向的胰岛素控制，目的是 防止或延迟胰腺切除术，而没有过多的副作用以及电流 治疗。