Abstract
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).
MeSH terms
-
Administration, Oral
-
Animals
-
Benzoin / analogs & derivatives
-
Benzoin / chemical synthesis
-
Benzoin / pharmacology*
-
Biological Availability
-
Cell Line
-
Cell Survival / drug effects
-
Diabetes Mellitus / enzymology
-
Diabetes Mellitus / metabolism
-
Drug Design
-
Enzyme Inhibitors / chemical synthesis
-
Enzyme Inhibitors / pharmacology*
-
Insecta
-
Mice
-
Mice, Knockout
-
Models, Animal
-
Protein Tyrosine Phosphatase, Non-Receptor Type 1
-
Protein Tyrosine Phosphatases / antagonists & inhibitors*
-
Structure-Activity Relationship
Substances
-
Enzyme Inhibitors
-
Protein Tyrosine Phosphatase, Non-Receptor Type 1
-
Protein Tyrosine Phosphatases
-
Ptpn1 protein, mouse
-
Benzoin