New Aminoimidazoles as β-Secretase (BACE-1) Inhibitors Showing Amyloid-β (Aβ) Lowering in Brain

被引：66

作者：

Gravenfors, Ylva ^{[1
]}

Viklund, Jenny ^{[1
]}

Blid, Jan ^{[1
]}

Ginman, Tobias ^{[1
]}

Karlstrom, Sofia ^{[1
]}

Kihlstrom, Jacob ^{[1
]}

Kolmodin, Karin ^{[1
]}

Lindstrom, Johan ^{[1
]}

von Berg, Stefan ^{[1
]}

von Kieseritzky, Fredrik ^{[1
]}

Slivo, Can ^{[1
]}

Swahn, Britt-Marie ^{[1
]}

Olsson, Lise-Lotte ^{[4
]}

Johansson, Patrik ^{[4
]}

Eketjall, Susanna ^{[2
]}

Falting, Johanna ^{[2
]}

Jeppsson, Fredrik ^{[2
]}

Stromberg, Kia ^{[2
]}

Janson, Juliette ^{[3
]}

Rahm, Fredrik ^{[1
]}

机构：

[1] AstraZeneca R&D, Dept Med Chem, SE-15185 Sodertalje, Sweden

[2] AstraZeneca R&D, Dept Neurosci, SE-15185 Sodertalje, Sweden

[3] AstraZeneca R&D, Dept DMPK, SE-15185 Sodertalje, Sweden

[4] AstraZeneca R&D, Discovery Sci, SE-43183 Molndal, Sweden

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 21期

关键词：

STRUCTURE-BASED DESIGN; AMMONIAK AUF KETONE; ALZHEIMERS-DISEASE; PRECURSOR PROTEIN; DISCOVERY; POTENT; IDENTIFICATION; REFINEMENT; REDUCTION; PROGRESS;

D O I：

10.1021/jm300991n

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Amino-2H-imidazoles are described as a new class of BACE-1 inhibitors for the treatment of Alzheimer's disease. Synthetic methods, crystal structures, and structure-activity relationships for target activity, permeability, and hERG activity are reported and discussed. Compound (S)-1m was one of the most promising compounds in this report, with high potency in the cellular assay and a good overall profile. When guinea pigs were treated with compound (S)-1m, a concentration and time dependent decrease in A beta 40 and A beta 42 levels in plasma, brain, and CSF was observed. The maximum reduction of brain A beta was 40-50%, 1.5 h after oral dosing (100 mu mol/kg). The results presented highlight the potential of this new class of BACE-1 inhibitors with good target potency and with low effect on hERG, in combination with a fair CNS exposure in vivo.

引用

页码：9297 / 9311

页数：15

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