Chem Biol Drug Des. 2012 Nov;80(5):775-80. doi: 10.1111/cbdd.12016. Epub 2012 Sep 10.
A series of 3, 5-disubstituted benzimidamides were synthesized and biologically evaluated as potential BACE1 inhibitors. Both the targeted compounds (benzimidamides) and the synthetic intermediates (benzonitriles) were tested for their BACE1 inhibitory activities in a cell-free FRET assay. All the synthesized benzimidamides were active as BACE1 inhibitors and compound 6d showed the lowest IC(50) value of 3.35 μm. Molecular docking study proposed a binding mode, which would help to the further optimization on 6d to achieve more potent, BBB penetrant BACE1 inhibitors.
我们合成了一系列 3,5-二取代苯并咪唑酰胺,并将其作为潜在的 BACE1 抑制剂进行了生物评估。在无细胞 FRET 测定中,我们测试了目标化合物(苯并咪唑酰胺)和合成中间体(苯甲腈)对 BACE1 的抑制活性。所有合成的苯并咪唑酰胺均具有 BACE1 抑制活性,化合物 6d 的 IC50 值最低,为 3.35μm。分子对接研究提出了一种结合模式,这将有助于进一步优化 6d,以获得更有效、更能穿透血脑屏障的 BACE1 抑制剂。