The development of potent non-peptidic PTP-1B inhibitors.
The SAR from our peptide libraries was exploited to design a series of potent deoxybenzoin PTP-1B inhibitors. The introduction of an ortho bromo substituent next to the difluoromethylphosphonate warhead gave up to 20-fold increase in potency compared to the desbromo analogues. In addition, these compounds were orally bioavailable and active in the animal models of non-insulin dependent diabetes mellitus (NIDDM).
Dufresne
Claude
C
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe-Claire, Dorval, Canada H9R 4P8. claude_l_dufresne@merck.com
Roy
Patrick
P
Wang
Zhaoyin
Z
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
Ramachandran
Chidambaram
C
Kennedy
Brian P
BP
Xu
Lijing
L
Gordon
Robert
R
Chan
Chi Chung
CC
Leblanc
Yves
Y
D000284:Administration, Oral; D000818:Animals; D001573:Benzoin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D001682:Biological Availability; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003920:Diabetes Mellitus / Q000201:enzymology / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D007313:Insecta; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse; D001573:Benzoin