Bicyclic and tricyclic thiophenes as protein tyrosine phosphatase 1B inhibitors.
A novel pyridothiophene inhibitor of PTP1B was discovered by rational screening of phosphotyrosine mimics at high micromolar concentrations. The potency of this lead compound has been improved significantly by medicinal chemistry guided by X-ray crystallography and molecular modeling. Excellent consistency has been observed between structure-activity relationships and structural information from PTP1B-inhibitor complexes.
Moretto
A F
AF
Chemical and Screening Science, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA.
Kirincich
S J
SJ
Xu
W X
WX
Smith
M J
MJ
Wan
Z-K
ZK
Wilson
D P
DP
Follows
B C
BC
Binnun
E
E
Joseph-McCarthy
D
D
Foreman
K
K
Erbe
D V
DV
Zhang
Y L
YL
Tam
S K
SK
Tam
S Y
SY
Lee
J
J
D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D013876:Thiophenes; D017027:Protein Tyrosine Phosphatases