The design and synthesis of human branched-chain amino acid aminotransferase inhibitors for treatment of neurodegenerative diseases.
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.
Hu
Lain-Yen
LY
Pfizer Global Research and Development, Ann Arbor, MI, USA. Lain-Yen.Hu@pfizer.com
Boxer
Peter A
PA
Kesten
Suzanne R
SR
Lei
Huangshu J
HJ
Wustrow
David J
DJ
Moreland
David W
DW
Zhang
Liming
L
Ahn
Kay
K
Ryder
Todd R
TR
Liu
Xiaohong
X
Rubin
John R
JR
Fahnoe
Kelly
K
Carroll
Richard T
RT
Dutta
Satavisha
S
Fahnoe
Douglass C
DC
Probert
Albert W
AW
Roof
Robin L
RL
Rafferty
Michael F
MF
Kostlan
Catherine R
CR
Scholten
Jeffrey D
JD
Hood
Molly
M
Ren
Xiao-Dan
XD
Schielke
Gerald P
GP
Su
Ti-Zhi
TZ
Taylor
Charles P
CP
Mistry
Anil
A
McConnell
Patrick
P
Hasemann
Charles
C
Ohren
Jeffrey
J
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*
D001572:Benzofurans; D004791:Enzyme Inhibitors; D013449:Sulfonamides; D018698:Glutamic Acid; D000637:Transaminases; C019798:branched-chain-amino-acid transaminase; D002118:Calcium