کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1369611 | 981784 | 2012 | 5 صفحه PDF | دانلود رایگان |

Recently, we reported substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. These inhibitors showed potent inhibitory activities in enzymatic and cell assays. We also designed and synthesized non-peptidic and small-sized inhibitors possessing a heterocyclic scaffold at the P2 position. By studying the structure–activity relationship of these inhibitors, we found that the σ–π interaction of an inhibitor with the BACE1-Arg235 side chain played a key role in the inhibition mechanism. Hence, we optimized the inhibitors with a focus on their P2 regions. In this Letter, a series of novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P2 position are described along with the results of the related structure–activity relationship study. These small-sized inhibitors are expected improved membrane permeability and bioavailability.
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Journal: Bioorganic & Medicinal Chemistry Letters - Volume 22, Issue 14, 15 July 2012, Pages 4640–4644