Nonpeptide, oral somatostatin agonists for congenital hyperinsulinemias

项目摘要 高胰岛素血症性低血糖（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、发育迟缓、学习障碍，甚至死亡。的最严重形式 HH是遗传性的，被称为先天性高胰岛素血症（CHI）。CHI主要是由关键基因突变引起的。 胰腺中胰岛中胰岛素分泌途径中的基因。 CHI的怀疑通过测试得到证实，包括需要实施高葡萄糖输注速率以维持 血糖水平正常目前，用于治疗CHI的唯一药物疗法是标签外使用。典型地， 首先尝试二氮嗪（一种胰岛素分泌抑制剂），尽管它通常无效，并且具有引起 在身体的大部分地方不正常的和过多的毛发生长。肽SST受体激动剂奥曲肽也是 标签外使用，用于对二氮嗪无反应或与反应差的患者联合使用。其 药理学特征（SST 2> SST 5）导致许多不希望的副作用，包括胰高血糖素的抑制 对CHI患者的最大需求有害的分泌，以及生长激素轴的抑制 在脑垂体尽管这些疗法的效果不佳，但它们仍在尝试，因为下一条治疗线通常是 部分或全部胰腺切除术即使手术成功，手术的结果也是病人变得 糖尿病患者，必须在其余生中积极管理葡萄糖。因此，一个重大的未满足的医疗需求 存在设计用于特异性和有效治疗CHI的药剂。 在这里，我们列出了我们的计划，以开发口服可用的，选择性的SST 5-，SST 3-，和/或双重SST 5/3激动剂， 治疗患有CHI和其他高胰岛素血症疾病的婴儿和儿童。这种化合物代表 这是CHI婴儿的一项重大进展，有望提供专门的胰岛素控制，目标是 预防或延迟胰腺切除术，而不会产生沿着电流的过多副作用 治疗。

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.