Synthesis and Target Identification of Potent GLP1 Secretagogues

描述(申请人提供)：目前还没有被批准的治疗2型糖尿病(T2 DM)的药物疗法是通过直接刺激肠道L细胞释放胰高血糖素样肽-1(GLP-1)来起作用的。识别这种潜在的抗糖尿病药物将具有非常重要的意义，因为肠道释放的GLP-1促进了胰腺胰岛素的分泌，同时也减缓了胃排空和抑制食欲。特别是，我们预计口服GLP-1促分泌剂将构成一类全新的降糖剂。与目前可用的GLP-1模拟物(例如埃塞那肽)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(例如西格列汀)联合使用时，它们将大幅提高循环中GLP-1的水平。我们有初步数据表明，我们的几个专有环alka[b]吲哚可以诱导具有良好EC50水平的mSTC-1细胞分泌GLP-1。这些小分子化合物可能是潜在的口服给药。这项合作提案的目标(参见Eli Lilly和George Holz教授的支持信；纽约州立大学北部医科大学)是为了发明新的化学方法(及其不对称变体)来访问环alka[b]吲哚，然后我们将使用这些方法来鉴定蛋白质靶标和发现更有效的GLP-1分泌物。我们的中心假设是，我们可以通过一种常见的吲哚碳正离子中间体快速获得环戊烷、环己烷和环七[b]吲哚。在适当的2-、3-或4-碳偶联伙伴存在下，吲哚碳正离子将发生(3+2)、(3+3)和(3+4)形式的环加成反应，得到所需的产物。这些目标将通过实现以下具体目标来实现：1)开发新的吲哚及相关杂环的环化方法，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分泌剂的生物靶点并寻找更有效的类似物。这一建议对人类健康的意义在于，它将导致新的分子实体的鉴定，这些新的分子实体可以诱导GLP-1释放的上调。这是朝着我们的长期目标迈出的第一步，即在提高GLP-1水平的基础上开发第一种T2 DM疗法。这项研究具有创新性，因为它利用未被充分利用的吲哚碳正离子作为新型三组分偶联反应的关键反应中间体，用于快速合成环醛[b]吲哚。我们还将开发第一个手性Bronsted酸催化氧基烯丙基或氨基烯丙基阳离子的(4+3)对映体选择性环加成反应的第一个例子。此外，环丙烷[b]吲哚和其他类似的杂环化合物已成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应用于非T2 DM治疗领域的候选药物的合成和鉴定。

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.