Sowaileh Munia F, Salyer Amy E, Roy Kuldeep K, John Jinu P, Woods James R, Doerksen Robert J, Hockerman Gregory H, Colby David A
Department of BioMolecular Sciences, University of Mississippi, University, MS 38677, United States.
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, United States.
Bioorg Med Chem Lett. 2018 Sep 1;28(16):2697-2700. doi: 10.1016/j.bmcl.2018.04.003. Epub 2018 Apr 7.
β-Hydroxy difluoromethyl ketones represent the newest class of agonists of the GABA-B receptor, and they are structurally distinct from all other known agonists at this receptor because they do not display the carboxylic acid or amino group of γ-aminobutyric acid (GABA). In this report, the design, synthesis, and biological evaluation of additional analogues of β-hydroxy difluoromethyl ketones characterized the critical nature of the substituted aromatic group on the lead compound. The importance of these new data is interpreted by docking studies using the X-ray structure of the GABA-B receptor. Moreover, we also report that the synthesis and biological evaluation of β-amino difluoromethyl ketones provided the most potent compound across these two series.
β-羟基二氟甲基酮是γ-氨基丁酸B（GABA-B）受体的最新一类激动剂，它们在结构上与该受体的所有其他已知激动剂不同，因为它们不具有γ-氨基丁酸（GABA）的羧酸或氨基。在本报告中，对β-羟基二氟甲基酮的其他类似物进行设计、合成和生物学评估，确定了先导化合物上取代芳基的关键性质。利用GABA-B受体的X射线结构通过对接研究解释了这些新数据的重要性。此外，我们还报告称，β-氨基二氟甲基酮的合成和生物学评估产生了这两个系列中最有效的化合物。
