Isothiazolidinone inhibitors of PTP1B containing imidazoles and imidazolines.
The structure-based design and synthesis of isothiazolidinone (IZD) inhibitors of PTP1B containing imidazoles and imidazolines and their modification to interact with the B site of PTP1B are described here. The X-ray crystal structures of 3I and 4I complexed with PTP1B were solved and revealed the inhibitors are interacting extensively with the B site of the enzyme.
Incyte Corporation, Discovery Chemistry, Experimental Station, Route 141 and Henry Clay Road, Wilmington, DE 19880, USA. bdouty@incyte.com
Brent
B
Douty
Brian
B
Wayland
Paul J
PJ
Ala
Michael J
MJ
Bower
James
J
Pruitt
Lori
L
Bostrom
Min
M
Wei
Ronald
R
Klabe
Lucie
L
Gonneville
Richard
R
Wynn
Timothy C
TC
Burn
Phillip C C
PC
Liu
Andrew P
AP
Combs
Eddy W
EW
Yue
D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D048288:Imidazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D007093:Imidazoles; D048288:Imidazolines; D013844:Thiazoles; C512915:isothiazolidinone; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1