Department of Pharmaceutical Technology and Process Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, Balanagar, Telangana, India.
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, Balanagar, Telangana, India.
Curr Med Chem. 2019;26(27):5207-5229. doi: 10.2174/0929867325666180406120051.
Adenosine 5'-monophosphate activated protein kinase (AMPK) is a key enzymatic protein involved in linking the energy sensing to the metabolic manipulation. It is a serine/threonine kinase activated by several upstream kinases. AMPK is a heterotrimeric protein complex regulated by AMP, ADP, and ATP allosterically. AMPK is ubiquitously expressed in various tissues of the living system such as heart, kidney, liver, brain and skeletal muscles. Thus malfunctioning of AMPK is expected to harbor several human pathologies especially diseases associated with metabolic and mitochondrial dysfunction. AMPK activators including synthetic derivatives and several natural products that have been found to show therapeutic relief in several animal models of disease. AMP, 5-Aminoimidazole-4-carboxamide riboside (AICA riboside) and A769662 are important activators of AMPK which have potential therapeutic importance in diabetes and diabetic complications. AMPK modulation has shown beneficial effects against diabetes, cardiovascular complications and diabetic neuropathy. The major impact of AMPK modulation ensures healthy functioning of mitochondria and energy homeostasis in addition to maintaining a strict check on inflammatory processes, autophagy and apoptosis. Structural studies on AMP and AICAR suggest that the free amino group is imperative for AMPK stimulation. A769662, a non-nucleoside thienopyridone compound which resulted from the lead optimization studies on A-592107 and several other related compound is reported to exhibit a promising effect on diabetes and its complications through activation of AMPK. Subsequent to the discovery of A769662, several thienopyridones, hydroxybiphenyls pyrrolopyridones have been reported as AMPK modulators. The review will explore the structure-function relationships of these analogues and the prospect of targeting AMPK in diabetes and diabetic complications.
腺苷 5'-单磷酸激活蛋白激酶 (AMPK) 是一种参与将能量感应与代谢调控联系起来的关键酶蛋白。它是一种丝氨酸/苏氨酸激酶，可被几种上游激酶激活。AMPK 是一种异源三聚体蛋白复合物，受 AMP、ADP 和 ATP 的变构调节。AMPK 在生命系统的各种组织中广泛表达，如心脏、肾脏、肝脏、大脑和骨骼肌。因此，AMPK 的功能障碍预计会导致几种人类病理，特别是与代谢和线粒体功能障碍相关的疾病。AMPK 激活剂包括合成衍生物和几种天然产物，已在几种疾病动物模型中显示出治疗缓解作用。AMP、5-氨基咪唑-4-甲酰胺核苷（AICA 核苷）和 A769662 是 AMPK 的重要激活剂，在糖尿病及其并发症中具有潜在的治疗意义。AMPK 调节已显示出对糖尿病、心血管并发症和糖尿病神经病变有益的作用。AMPK 调节的主要影响确保了线粒体的健康功能和能量平衡，此外还对炎症过程、自噬和细胞凋亡进行严格控制。对 AMP 和 AICAR 的结构研究表明，游离氨基对 AMPK 的刺激是必不可少的。A769662 是一种非核苷噻吩并吡啶酮化合物，是在对 A-592107 和其他几种相关化合物进行先导优化研究的基础上开发的，据报道，它通过激活 AMPK 对糖尿病及其并发症有显著的治疗作用。在发现 A769662 之后，已经报道了几种噻吩并吡啶酮、羟基联苯吡咯并吡啶酮作为 AMPK 调节剂。该综述将探讨这些类似物的结构-功能关系以及靶向 AMPK 治疗糖尿病和糖尿病并发症的前景。
