Institute for Research in Biomedicine, Barcelona - Chemistry and Molecular Pharmacology, Spain.
Expert Opin Ther Pat. 2011 Nov;21(11):1693-741. doi: 10.1517/13543776.2011.627325.
The serine exopeptidase DPP IV is a dual protein able to work as an enzyme and an interacting protein. The incretin molecules glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are hydrolyzed by DPP IV into inactive forms, which are unable to promote insulin secretion. Therefore, DPP IV is a validated target for the treatment of type 2 diabetes mellitus (T2DM), and a number of inhibitors have been reported in the literature as antidiabetic drugs.
DPP IV inhibitor patents from 2006 are included in this review. Documents are classified into chemical groups depending on the main claim. Groups are: i) pyrrolidines and thiazolidines; ii) cyclohexanes, piperidines, piperazines, pyridines and pyrimidines; iii) fused 5-carbon cycles; iv) pyridine, pyrimidine and pyrazine-based bicyclic structures; v) indoles, condensed-imidazoles and xanthines; vi) pyrido-pyrimidines, quinolones, isoquinolines, quinozalines, quinoxalines, naphthyridines, quinolones and quinazolinones; vii) benzoquinolizines, fused aminopiperidines and fused triazoles; viii) other heterocyclic structures and ix) peptidomimetics.
Research in finding new DPP IV inhibitors is intense, despite the number of reported molecules. This is mainly because marketed compounds have been approved in the last 5 years and long-term side effects have not been detected. The perfect inhibitor for the T2DM treatment would therefore be a molecule that inhibits GLP-1 and GIP degradation by DPP IV, but does not affect the activity of the protease in other substrates, nor disturbs the communication of DPP IV with other proteins.
丝氨酸外肽酶 DPP IV 是一种双重蛋白，既能作为酶又能作为相互作用蛋白发挥作用。肠促胰岛素分子胰高血糖素样肽 1（GLP-1）和葡萄糖依赖性胰岛素促分泌肽（GIP）被 DPP IV 水解成无活性形式，无法促进胰岛素分泌。因此，DPP IV 是治疗 2 型糖尿病（T2DM）的有效靶点，文献中已有多种抑制剂被报道为抗糖尿病药物。
本综述包括 2006 年的 DPP IV 抑制剂专利。根据主要权利要求，文献分为化学基团。组分类如下：i）吡咯烷和噻唑烷；ii）环己烷、哌啶、哌嗪、吡啶和嘧啶；iii）融合的 5 碳环；iv）吡啶、嘧啶和吡嗪基双环结构；v）吲哚、稠合咪唑和黄嘌呤；vi）吡啶并嘧啶、喹诺酮、异喹啉、喹唑啉、喹喔啉、萘啶、喹诺酮和喹唑啉酮；vi）苯并喹啉嗪、融合氨基哌啶和融合三唑；vii）其他杂环结构和 ix）肽模拟物。
尽管已报道的分子数量众多，但寻找新的 DPP IV 抑制剂的研究仍很活跃。这主要是因为上市化合物在过去 5 年中已获得批准，尚未发现长期副作用。因此，治疗 T2DM 的理想抑制剂将是一种既能抑制 DPP IV 对 GLP-1 和 GIP 的降解，又不影响蛋白酶在其他底物中的活性，也不干扰 DPP IV 与其他蛋白质之间的通讯的分子。
