کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1377116 | 981971 | 2008 | 5 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: BACE1 inhibitors: Optimization by replacing the P1′ residue with non-acidic moiety BACE1 inhibitors: Optimization by replacing the P1′ residue with non-acidic moiety](/preview/png/1377116.png)
Recently, we reported potent BACE1 inhibitors KMI-429, -684, and -574 possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. These inhibitors showed potent inhibitory activities in enzymatic and cell assays, especially, KMI-429 was confirmed to significantly inhibit Aβ production in vivo. However, acidic moieties at the P4 and P1′ positions of KMI-compounds were thought to be unfavorable for membrane permeability across the blood–brain barrier. Herein, we replaced acidic moieties at the P4 position with other hydrogen bond acceptor groups, and these inhibitors exhibited improved BACE1 inhibitory activities in cultured cells. In this study, we replaced the acidic moieties at the P1′ position with non-acidic and low molecular sized moieties.
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Journal: Bioorganic & Medicinal Chemistry Letters - Volume 18, Issue 5, 1 March 2008, Pages 1649–1653