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The design and synthesis of human branched-chain amino acid aminotransferase inhibitors for treatment of neurodegenerative diseases |
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| Authors: | Hu Lain-Yen Boxer Peter A Kesten Suzanne R Lei Huangshu J Wustrow David J Moreland David W Zhang Liming Ahn Kay Ryder Todd R Liu Xiaohong Rubin John R Fahnoe Kelly Carroll Richard T Dutta Satavisha Fahnoe Douglass C Probert Albert W Roof Robin L Rafferty Michael F Kostlan Catherine R Scholten Jeffrey D Hood Molly Ren Xiao-Dan Schielke Gerald P Su Ti-Zhi Taylor Charles P Mistry Anil McConnell Patrick Hasemann Charles Ohren Jeffrey |
| Institution: | Pfizer Global Research and Development, Ann Arbor, MI, USA. Lain-Yen.Hu@pfizer.com |
| Abstract: | 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 microM 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. |
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