Synthesis and Target Identification of Potent GLP1 Secretagogues

有效 GLP1 促分泌剂的合成和靶点鉴定

• 批准号: 9042399
• 负责人: JIMMY WU
• 金额: $ 30.67万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9042399
• 关键词: Acids; Area; Attenuated; Biological; Blood Glucose; Carbon; Cations; Cells; Chemicals; Collaborations; Core Facility; Coupling; Data; Desire for food; Development; Drug Industry; Feeling; G-Protein-Coupled Receptors; GCG gene; Gastric Emptying; Glucagon; Glucose; Goals; Half-Life; Health; Health Care Costs; Human; Indoles; Intestinal Secretions; Intestines; Ion Channel Protein; L Cells; Lead; Letters; Marketing; Medical; Methodology; Methods; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Pharmaceutical Preparations; Pharmacotherapy; Phosphoric Acids; Production; Proteins; Proteomics; Public Health; Reaction; Research; Satiation; Subcutaneous Injections; Therapeutic; United States; Universities; Up-Regulation; Variant; Work; analog; base; cycloaddition; drug candidate; exenatide; fischerindole; glucagon-like peptide; inhibitor/antagonist; innovation; insulin secretion; interest; mimetics; novel; novel therapeutics; pandemic disease; small molecule

DESCRIPTION (provided by applicant): There are presently no approved drug therapies for type 2 diabetes mellitus (T2DM) that operate by directly stimulating the release of glucagon-like peptide-1 (GLP-1) from intestinal L-cells. Identifying such potentially antidiabetogenic agents would be highly significant due to the fact that intestinally released GLP-1 enhances pancreatic insulin secretion while also slowing gastric emptying and suppressing appetite. In particular, we expect that orally administered GLP-1 secretagogues would constitute an entirely new class of blood glucose-lowering agents. Unlike currently available GLP-1 mimetics (e.g., exenatide), they would not require subcutaneous injection, and when combined with DPP-4 inhibitors that extend the half-life of GLP-1 (e.g., sitagliptin), they would raise levels of circulating GLP-1 substantialy. We have preliminary data that indicate several of our proprietary cycloalka[b]indoles can induce the secretion of GLP-1 in mSTC-1 cells with good EC50 levels. These are small-molecule compounds that may potentially be orally administrable. The objectives for this collaborative proposal (see letters of support from Eli Lilly and Prof. George Holz; SUNY Upstate Medical University) are to invent novel chemical methods (and their asymmetric variants) for accessing cycloalka[b]indoles which we will then use for protein target identification and the discovery of more potent GLP-1 secretagogues. Our central hypothesis is that we can rapidly access cyclopenta-, cyclohexa- and cyclohepta[b]indoles through a common indolyl carbocation intermediate. In the presence of appropriate 2-, 3-, or 4-carbon coupling partners, indolyl carbocations will undergo (3+2), (3+3), and (3+4) formal cycloaddition reactions to furnish the desired products. These objectives will be accomplished by carrying out the following specific aims: 1) develop new annulation methods for indole and related heterocycles, 2) develop asymmetric annulation reactions of indole and related heterocycles, and 3) determine the biological target of these GLP-1 secretagogues and identify more potent analogues. The significance of this proposal to human health is that it will lead to the identification of new molecular entities that can induce the up-regulation of GLP-1 release. This is the initial step towards our long-term goal of developing the 1st T2DM therapeutic based on increasing GLP-1 levels. This research is innovative because it exploits under-utilized indolyl carbocations as key reactive intermediates in novel three-component coupling reactions for the rapid syntheses of cycloalka[b]indoles. We will validate this methodology by featuring it as the key step in the 1st total synthesis of fischerindole L. We will also develop the 1st example of an enantioselective (4+3) cycloaddition reaction of oxyallyl or aminoallyl cations catalyzed by chiral Bronsted acids. Moreover, cycloalka[b]indoles and other similar heterocycles have been targeted as potential drug candidates for numerous other indications. Therefore, an additional potential positive impact of this work is its application to the syntheses and identification of drug candidates in non-T2DM therapeutic areas.

描述（由申请人提供）：目前尚无通过直接刺激肠L细胞释放胰高血糖素样肽-1（GLP-1）来治疗2型糖尿病（T2 DM）的获批药物。鉴定这种潜在的抗糖尿病药物将是非常重要的，因为经尿道释放的GLP-1增强胰腺胰岛素分泌，同时还减缓胃排空和抑制食欲。特别是，我们预计口服给药的GLP-1促分泌素将构成一类全新的降血糖剂。与目前可用的GLP-1模拟物（例如，艾塞那肽），它们不需要皮下注射，并且当与延长GLP-1半衰期的DPP-4抑制剂（例如，西格列汀），它们将显著提高循环GLP-1的水平。我们的初步数据表明，我们的几种专利环烷基[B]吲哚类化合物可以诱导mSTC-1细胞分泌GLP-1，并具有良好的EC 50水平。这些是可能口服给药的小分子化合物。该合作提案的目标（见Eli Lilly和乔治Holz教授（SUNY Upstate Medical University）的支持信）是发明用于获得环烷基[B]吲哚的新型化学方法（及其不对称变体），然后我们将其用于蛋白质靶标鉴定和发现更有效的GLP-1促分泌素。我们的中心假设是，我们可以通过一个共同的吲哚基碳正离子中间体快速获得环戊，环己和环庚[B]吲哚。在适当的2-、3-或4-碳偶联配偶体的存在下，吲哚基碳阳离子将经历（3+2）、（3+3）和（3+4）形式环加成反应以提供所需产物。这些目标将通过实现以下具体目标来实现：1）开发吲哚和相关杂环的新成环方法，2）开发吲哚和相关杂环的不对称成环反应，以及3）确定这些GLP-1促分泌素的生物靶标并鉴定更有效的类似物。该提案对人类健康的重要性在于，它将导致鉴定可诱导GLP-1释放上调的新分子实体。这是我们实现长期目标的第一步，即开发基于增加GLP-1水平的第一种T2 DM治疗药物。本研究是创新的，因为它利用未充分利用的吲哚基碳正离子作为关键的活性中间体，在新的三组分偶联反应的快速合成环烷基[B]吲哚。我们将此方法作为首次全合成Fischerindole L的关键步骤进行验证。我们还将开发的手性布朗斯台德酸催化的氧烯丙基或氨基烯丙基阳离子的对映选择性（4+3）环加成反应的第一个例子。此外，环烷基[B]吲哚和其他类似的杂环已被靶向作为用于许多其他适应症的潜在药物候选物。因此，这项工作的另一个潜在的积极影响是它在非T2 DM治疗领域的候选药物的合成和鉴定中的应用。