Synthesis and Target Identification of Potent GLP1 Secretagogues

描述（由申请人提供）：目前还没有通过直接刺激胰高血糖素样肽-1 （GLP-1）从肠l细胞释放来治疗2型糖尿病（T2DM）的药物。由于肠道释放的GLP-1可以促进胰腺胰岛素分泌，同时也可以减缓胃排空和抑制食欲，因此确定这种潜在的抗糖尿病药物将是非常重要的。特别是，我们预计口服GLP-1分泌剂将构成一个全新的一类降糖药。与目前可用的GLP-1模拟物（如艾塞那肽）不同，它们不需要皮下注射，当与延长GLP-1半衰期的DPP-4抑制剂（如西格列汀）联合使用时，它们会显著提高循环GLP-1的水平。我们有初步数据表明，我们专有的几种cycloalka[b]吲哚可以诱导具有良好EC50水平的mSTC-1细胞分泌GLP-1。这些都是可能口服的小分子化合物。这项合作提案的目标（见Eli Lilly和George Holz教授的支持信；SUNY上州医科大学）是发明新的化学方法（及其不对称变体）来获取环alka[b]吲哚，然后我们将其用于蛋白质靶标鉴定和发现更有效的GLP-1分泌物。我们的中心假设是，我们可以通过一个常见的吲哚碳正离子中间体快速获得环五，环己和环七[b]吲哚。在适当的2-、3-或4-碳偶联伙伴存在的情况下，吲哚基碳阳离子将经历（3+2）、（3+3）和（3+4）形式环加成反应，以提供所需的产物。这些目标将通过以下具体目标来实现：1)开发吲哚及相关杂环的新环化方法；2)开发吲哚及相关杂环的不对称环化反应；3)确定这些GLP-1分泌物的生物学靶点并鉴定更有效的类似物。这一提议对人类健康的意义在于，它将导致鉴定出能够诱导GLP-1释放上调的新分子实体。这是我们开发第一种基于提高GLP-1水平的T2DM治疗的长期目标的第一步。这项研究具有创新性，因为它利用了未充分利用的吲哚基碳阳离子作为新型三组分偶联反应的关键反应中间体，用于快速合成cycloalka[b]吲哚。我们将通过将其作为第一次全合成费切吲哚l的关键步骤来验证这一方法。我们还将开发手性Bronsted酸催化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[b]吲哚和其他类似的杂环化合物已被作为许多其他适应症的潜在候选药物。因此，这项工作的另一个潜在的积极影响是它在非2型糖尿病治疗领域的候选药物的合成和鉴定中的应用。

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.