Ghosh Arun K, Brindisi Margherita, Yen Yu-Chen, Xu Xiaoming, Huang Xiangping, Devasamudram Thippeswamy, Bilcer Geoffrey, Lei Hui, Koelsch Gerald, Mesecar Andrew D, Tang Jordan
Department of Chemistry, Purdue University, West Lafayette, IN 47907, United States; Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, United States; Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, United States.
Department of Chemistry, Purdue University, West Lafayette, IN 47907, United States; Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, United States.
Bioorg Med Chem Lett. 2015 Feb 1;25(3):668-72. doi: 10.1016/j.bmcl.2014.11.087. Epub 2014 Dec 6.
We describe structure-based design, synthesis, and biological evaluation of a series of novel inhibitors bearing a pyrazole (compounds 3a-h) or a thiazole moiety (compounds 4a-e) as the P3 ligand. We have also explored Boc-β-amino-l-alanine as a novel P2 ligand. A number of inhibitors have displayed β-secretase inhibitory potency. Inhibitor 4c has shown potent BACE1 inhibitory activity, Ki=0.25nM, cellular EC50 of 194nM, and displayed good selectivity over BACE2. A model of 4c was created based upon the X-ray structure of 2-bound β-secretase which revealed critical interactions in the active site.
我们描述了一系列以吡唑（化合物3a - h）或噻唑部分（化合物4a - e）作为P3配体的新型抑制剂的基于结构的设计、合成及生物学评价。我们还探索了Boc-β-氨基-L-丙氨酸作为新型P2配体。许多抑制剂已显示出β-分泌酶抑制活性。抑制剂4c表现出强效的BACE1抑制活性，Ki = 0.25 nM，细胞EC50为194 nM，并且对BACE2具有良好的选择性。基于与2结合的β-分泌酶的X射线结构创建了4c的模型，该模型揭示了活性位点中的关键相互作用。
