School of Natural Sciences, Griffith University, Brisbane, Qld, 4111, Australia.
Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Qld, 4111, Australia.
Eur J Med Chem. 2017 Feb 15;127:341-356. doi: 10.1016/j.ejmech.2016.12.049. Epub 2016 Dec 26.
Glycogen Phosphorylase (GP) is a functionally active dimeric enzyme, which is a target for inhibition of the conversion of glycogen to glucose-1-phosphate. In this study we report the design and synthesis of 14 new pyridone derivatives, and seek to extend the SAR analysis of these compounds. The SAR revealed the minor influence of the amide group, importance of the pyridone ring both spatially around the pyridine ring and for possible π-stacking, and confirmed a preference for inclusion of 3,4-dichlorobenzyl moieties, as bookends to the pyridone scaffold. Upon exploring a dimer strategy as part of the SAR analysis, the first extended 2-oxo-dihydropyridinyl-3-yl amide nanomolar based inhibitors of GPa (IC = 230 and 260 nM) were identified.
糖原磷酸化酶（GP）是一种具有功能活性的二聚体酶，可作为抑制将糖原转化为葡萄糖-1-磷酸的靶标。在这项研究中，我们报告了 14 种新的吡啶酮衍生物的设计和合成，并寻求扩展这些化合物的 SAR 分析。SAR 揭示了酰胺基团的影响较小，吡啶酮环在吡啶环周围的空间以及可能的 π-堆积的重要性，并且证实了包含 3,4-二氯苄基部分的偏好，作为吡啶酮支架的书挡。在探索作为 SAR 分析一部分的二聚体策略时，首次鉴定出基于 2-氧代-二氢吡啶基-3-基酰胺的纳摩尔级别的 GPα（IC = 230 和 260 nM）抑制剂。
