噻吩取代的酰基胍类作为β-分泌酶1（BACE1）抑制剂
Thiophene substituted acylguanidines as BACE1 inhibitors.
作者信息
Fobare William F, Solvibile William R, Robichaud Albert J, Malamas Michael S, Manas Eric, Turner Jim, Hu Yun, Wagner Erik, Chopra Rajiv, Cowling Rebecca, Jin Guixan, Bard Jonathan
机构信息
Chemical and Screening Sciences, Wyeth Research, CN8000, Princeton, NJ 08543-8000, USA.
出版信息
Bioorg Med Chem Lett. 2007 Oct 1;17(19):5353-6. doi: 10.1016/j.bmcl.2007.08.010. Epub 2007 Aug 11.
A series of thiophene-substituted acylguanidines were designed from a pyrrole substituted acylguanidine HTS lead. This template allowed a greater flexibility, through differential Suzuki couplings, to explore the binding site of BACE1 and to enhance the inhibitory potencies. This exploration provided a 25-fold enhancement in potency to yield compound 10a, which was 150 nM in a BACE1 FRET assay.
一系列噻吩取代的酰基胍是从吡咯取代的酰基胍高通量筛选先导化合物设计而来。通过不同的铃木耦合反应，该模板具有更大的灵活性，可用于探索β-分泌酶1（BACE1）的结合位点并提高抑制活性。这种探索使活性提高了25倍，得到化合物10a，其在BACE1荧光共振能量转移（FRET）测定中的活性为150 nM。
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