8-Tetrahydropyran-2-yl Chromans: Highly Selective Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors

被引：15

作者：

Thomas, Allen A. ^{[1
]}

Hunt, Kevin W. ^{[1
]}

Newhouse, Brad ^{[1
]}

Watts, Ryan J. ^{[2
]}

Liu, Xingrong ^{[2
]}

Vigers, Guy ^{[1
]}

Smith, Darin ^{[1
]}

Rhodes, Susan P. ^{[1
]}

Brown, Karin D. ^{[1
]}

Otten, Jennifer N. ^{[1
]}

Burkard, Michael ^{[1
]}

Cox, April A. ^{[1
]}

Do, Mary K. Geck ^{[1
]}

Dutcher, Darrin ^{[1
]}

Rana, Sumeet ^{[1
]}

DeLisle, Robert K. ^{[1
]}

Regal, Kelly ^{[1
]}

Wright, Albion D. ^{[1
]}

Groneberg, Robert ^{[1
]}

Liao, Jiangpeng ^{[3
]}

Scearce-Levie, Kimberly ^{[2
]}

Siu, Michael ^{[2
]}

Purkey, Hans E. ^{[2
]}

Lyssikatos, Joseph P. ^{[2
]}

机构：

[1] Array BioPharma, Boulder, CO 80301 USA

[2] Genentech Inc, San Francisco, CA 94080 USA

[3] WuXi AppTec Co Ltd, Shanghai 200131, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 23期

关键词：

ALZHEIMERS-DISEASE; IN-VIVO; SECRETASE INHIBITORS; ASPARTIC PROTEASE; IODINE ISOCYANATE; SS-SECRETASE; CATHEPSIN-D; DESIGN; BRAIN; AMINOIMIDAZOLES;

D O I：

10.1021/jm5015132

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 2,3,4,4a,10,10a-hexahydropyrano[3,2-b]chromene analogs was developed that demonstrated high selectivity (>2000-fold) for BACE1 vs Cathepsin D (CatD). Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Guided by structure based design, changes to P2' and P3 moieties were explored. A conformationally restricted P2' methyl group provided inhibitors with excellent cell potency (37137 nM) and selectivity (435 to >2000-fold) for BACE1 vs CatD. These efforts lead to compound 59, which demonstrated a 69% reduction in rat CSF A beta(1-40) at 60 mg/kg (PO).

引用

页码：10112 / 10129

页数：18

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