PMID- 11881998
OWN - NLM
STAT- MEDLINE
DCOM- 20020426
LR  - 20190710
IS  - 0022-2623 (Print)
IS  - 0022-2623 (Linking)
VI  - 45
IP  - 6
DP  - 2002 Mar 14
TI  - First non-ATP competitive glycogen synthase kinase 3 beta (GSK-3beta) inhibitors: 
      thiadiazolidinones (TDZD) as potential drugs for the treatment of Alzheimer's 
      disease.
PG  - 1292-9
AB  - Glycogen synthase kinase 3 beta (GSK-3beta) has a central role in Alzheimer's 
      disease (AD). Selective inhibitors which avoid tau hyperphosphorylation may 
      represent an effective therapeutical approach to the AD pharmacotherapy and other 
      neurodegenerative disorders. Here, we describe the synthesis, biological 
      evaluation, and SAR of the small heterocyclic thiadiazolidinones (TDZD) as the 
      first non-ATP competitive inhibitor of GSK-3beta. Their synthesis is based on the 
      reactivity of sulfenyl chlorides. In GSK-3beta assays, TDZD derivatives showed 
      IC(50) values in the micromolar range, whereas in other protein kinases assays 
      they were devoid of any inhibitory activity. SAR studies allowed the 
      identification of the key structural features. Finally, a possible enzymatic 
      binding mode is proposed.
FAU - Martinez, Ana
AU  - Martinez A
AD  - Instituto de Quimica Medica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain. 
      iqmam06@pinar2.csic.es
FAU - Alonso, Mercedes
AU  - Alonso M
FAU - Castro, Ana
AU  - Castro A
FAU - Perez, Concepcion
AU  - Perez C
FAU - Moreno, Francisco J
AU  - Moreno FJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Thiadiazoles)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 2.7.11.- (Glycogen Synthase Kinases)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Alzheimer Disease/*drug therapy
MH  - Amino Acid Sequence
MH  - Animals
MH  - Binding, Competitive
MH  - Calcium-Calmodulin-Dependent Protein Kinases/*antagonists & inhibitors
MH  - Enzyme Inhibitors/*chemical synthesis/*pharmacology
MH  - Glycogen Synthase Kinase 3
MH  - Glycogen Synthase Kinases
MH  - Humans
MH  - Molecular Sequence Data
MH  - Rabbits
MH  - Rats
MH  - Structure-Activity Relationship
MH  - Thiadiazoles/*chemical synthesis/*pharmacology
EDAT- 2002/03/08 10:00
MHDA- 2002/04/27 10:01
CRDT- 2002/03/08 10:00
PHST- 2002/03/08 10:00 [pubmed]
PHST- 2002/04/27 10:01 [medline]
PHST- 2002/03/08 10:00 [entrez]
AID - jm011020u [pii]
AID - 10.1021/jm011020u [doi]
PST - ppublish
SO  - J Med Chem. 2002 Mar 14;45(6):1292-9. doi: 10.1021/jm011020u.