Design and Synthesis of Potent and Selective BACE-1 Inhibitors

被引：26

作者：

Bjorklund, Catarina ^{[1
]}

Oscarson, Stefan ^{[1
,2
]}

Benkestock, Kurt ^{[3
]}

Borkakoti, Neera ^{[3
]}

Jansson, Katarina ^{[3
]}

Lindberg, Jimmy ^{[3
]}

Vrang, Lotta ^{[3
]}

Hallberg, Anders ^{[4
]}

Rosenquist, Asa ^{[3
]}

Samuelsson, Bertil ^{[1
,3
]}

机构：

[1] Stockholm Univ, Arrhenius Lab, Dept Organ Chem, SE-10691 Stockholm, Sweden

[2] UCD, Sch Chem & Chem Biol, Dublin 4, Ireland

[3] Medivir AB, SE-14122 Huddinge, Sweden

[4] Uppsala Univ, Dept Med Chem, BMC, SE-75123 Uppsala, Sweden

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 04期

关键词：

HIV-1 PROTEASE INHIBITORS; BETA-SECRETASE; ALZHEIMERS-DISEASE; ASPARTIC PROTEASE; PLASMEPSIN-II; CATHEPSIN-D; BRAIN; MICE;

D O I：

10.1021/jm901168f

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Highly potent BACE-1 protease inhibitors have been developed from ill inhibitors containing a hydroxyethylene (HE) core displaying aryloxymethyl or benzyloxymethyl P1 side chain and a methoxy P1' side chain. The target molecules were synthesized in good overall yields from chiral carbohydrate starting materials. The inhibitors show high BACF-1 potency and good selectivity against cathepsin D, where the most potent inhibitor Furnishes BACE-1 Ki << 1 nM and displays > 1000-fold selectivity over cathepsin D.

引用

页码：1458 / 1464

页数：7

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