Structure based design of a series of potent and selective non peptidic PTP-1B inhibitors.
A series of benzotriazole phenyldifluoromethylphosphonic acids were found to be potent PTP-1B inhibitors. Molecular modeling on the X-ray crystal structure of the lead structure led to the design of potent PTP-1B inhibitors that show moderate selectivity against TC-PTP, a very closely related protein tyrosine phosphatase.
Lau
Cheuk K
CK
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Quebec H9R 4P8, Canada. lau@merck.com
Bayly
Christopher I
CI
Gauthier
Jacques Yves
JY
Li
Chun Sing
CS
Therien
Michel
M
Asante-Appiah
Ernest
E
Cromlish
Wanda
W
Boie
Yves
Y
Forghani
Farnaz
F
Desmarais
Sylvie
S
Wang
Qingping
Q
Skorey
Kathryn
K
Waddleton
Deena
D
Payette
Paul
P
Ramachandran
Chidambaram
C
Kennedy
Brian P
BP
Scapin
Giovana
G
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007313:Insecta; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D015394:Molecular Structure; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D009943:Organophosphorus Compounds; C032627:methylphosphonic acid; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse