1.
Bioorg Med Chem Lett
; 14(4): 1039-42, 2004 Feb 23.
Article
in English
| MEDLINE
| ID: mdl-15013019
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).
Subject(s)
Benzoin/pharmacology , Enzyme Inhibitors/pharmacology , Protein Tyrosine Phosphatases/antagonists & inhibitors , Administration, Oral , Animals , Benzoin/analogs & derivatives , Benzoin/chemical synthesis , Biological Availability , Cell Line , Cell Survival/drug effects , Diabetes Mellitus/enzymology , Diabetes Mellitus/metabolism , Drug Design , Enzyme Inhibitors/chemical synthesis , Insecta , Mice , Mice, Knockout , Models, Animal , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Structure-Activity Relationship
2.
Bioorg Med Chem Lett
; 14(4): 1043-8, 2004 Feb 23.
Article
in English
| MEDLINE
| ID: mdl-15013020
ABSTRACT
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.
