title: The design and synthesis of human branched-chain amino acid aminotransferase inhibitors for treatment of neurodegenerative diseases.
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.
authors.affiliation: Pfizer Global Research and Development, Ann Arbor, MI, USA. Lain-Yen.Hu@pfizer.com
authors.forename: Lain-Yen
authors.initials: LY
authors.lastname: Hu
authors.forename: Peter A
authors.initials: PA
authors.lastname: Boxer
authors.forename: Suzanne R
authors.initials: SR
authors.lastname: Kesten
authors.forename: Huangshu J
authors.initials: HJ
authors.lastname: Lei
authors.forename: David J
authors.initials: DJ
authors.lastname: Wustrow
authors.forename: David W
authors.initials: DW
authors.lastname: Moreland
authors.forename: Liming
authors.initials: L
authors.lastname: Zhang
authors.forename: Kay
authors.initials: K
authors.lastname: Ahn
authors.forename: Todd R
authors.initials: TR
authors.lastname: Ryder
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Liu
authors.forename: John R
authors.initials: JR
authors.lastname: Rubin
authors.forename: Kelly
authors.initials: K
authors.lastname: Fahnoe
authors.forename: Richard T
authors.initials: RT
authors.lastname: Carroll
authors.forename: Satavisha
authors.initials: S
authors.lastname: Dutta
authors.forename: Douglass C
authors.initials: DC
authors.lastname: Fahnoe
authors.forename: Albert W
authors.initials: AW
authors.lastname: Probert
authors.forename: Robin L
authors.initials: RL
authors.lastname: Roof
authors.forename: Michael F
authors.initials: MF
authors.lastname: Rafferty
authors.forename: Catherine R
authors.initials: CR
authors.lastname: Kostlan
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Scholten
authors.forename: Molly
authors.initials: M
authors.lastname: Hood
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Ren
authors.forename: Gerald P
authors.initials: GP
authors.lastname: Schielke
authors.forename: Ti-Zhi
authors.initials: TZ
authors.lastname: Su
authors.forename: Charles P
authors.initials: CP
authors.lastname: Taylor
authors.forename: Anil
authors.initials: A
authors.lastname: Mistry
authors.forename: Patrick
authors.initials: P
authors.lastname: McConnell
authors.forename: Charles
authors.initials: C
authors.lastname: Hasemann
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ohren
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D018698:Glutamic Acid / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D015394:Molecular Structure; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D000637:Transaminases / Q000037:antagonists & inhibitors*
chemical_list: D001572:Benzofurans; D004791:Enzyme Inhibitors; D013449:Sulfonamides; D018698:Glutamic Acid; D000637:Transaminases; C019798:branched-chain-amino-acid transaminase; D002118:Calcium