The design and synthesis of human branched-chain amino acid aminotransferase inhibitors for treatment of neurodegenerative diseases

被引：25

作者：

Hu, LY ^{[1
]}

Boxer, PA ^{[1
]}

Kesten, SR ^{[1
]}

Lei, HSJ ^{[1
]}

Wustrow, DJ ^{[1
]}

Moreland, DW ^{[1
]}

Zhang, LM ^{[1
]}

Ahn, K ^{[1
]}

Ryder, TR ^{[1
]}

Liu, XH ^{[1
]}

Rubin, JR ^{[1
]}

Fahnoe, K ^{[1
]}

Carroll, RT ^{[1
]}

Dutta, S ^{[1
]}

Fahnoe, DC ^{[1
]}

Probert, AW ^{[1
]}

Roof, RL ^{[1
]}

Rafferty, MF ^{[1
]}

Kostlan, CR ^{[1
]}

Scholten, JD ^{[1
]}

Hood, M ^{[1
]}

Ren, XD ^{[1
]}

Schielke, GP ^{[1
]}

Su, TZ ^{[1
]}

Taylor, CP ^{[1
]}

Mistry, A ^{[1
]}

McConnell, P ^{[1
]}

Hasemann, C ^{[1
]}

Ohren, J ^{[1
]}

机构：

[1] Pfizer Global Res & Dev, Ann Arbor, MI USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 09期

关键词：

D O I：

10.1016/j.bmcl.2005.07.058

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The inhibition of the cytosolic isoenzyme BCAT that is expressed specifically in neuronal tissue is likely to be useful for the treatment of neurodegenerative and other neurological disorders where glutamatergic mechanisms are implicated. Compound 2 exhibited an IC50 of 0.8 mu M in the hBCATc assays; it is an active and selective inhibitor. Inhibitor 2 also blocked calcium influx into neuronal cells following inhibition of glutamate uptake, and demonstrated neuroprotective efficacy in vivo. SAR, pharmacology, and the crystal structure of hBCATc with inhibitor 2 are described. (C) 2005 Elsevier Ltd. All rights reserved.

引用

页码：2337 / 2340

页数：4

共 9 条

[1] Overexpression and characterization of the human mitochondrial and cytosolic branched-chain aminotransferases [J].