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 com...

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Published inBioorganic & medicinal chemistry letters Vol. 14; no. 4; pp. 1039 - 1042
Main Authors DUFRESNE, Claude, ROY, Patrick, WADDLETON, Deena, RAMACHANDRAN, Chidambaram, KENNEDY, Brian P, LIJING XU, GORDON, Robert, CHI CHUNG CHAN, LEBLANC, Yves, ZHAOYIN WANG, ASANTE-APPIAH, Ernest, CROMLISH, Wanda, BOIE, Yves, FORGHANI, Farnaz, DESMARAIS, Sylvie, QINGPING WANG, SKOREY, Kathryn
Format Journal Article
LanguageEnglish
Published Oxford Elsevier 23.02.2004
Subjects
Administration, Oral
Animals
Benzoin - analogs & derivatives
Benzoin - chemical synthesis
Benzoin - pharmacology
Biological and medical sciences
Biological Availability
Cell Line
Cell Survival - drug effects
Diabetes Mellitus - enzymology
Diabetes Mellitus - metabolism
Drug Design
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - pharmacology
General and cellular metabolism. Vitamins
Insecta
Medical sciences
Mice
Mice, Knockout
Models, Animal
Pharmacology. Drug treatments
Protein Tyrosine Phosphatase, Non-Receptor Type 1
Protein Tyrosine Phosphatases - antagonists & inhibitors
Structure-Activity Relationship
Type 2 diabetes
Endocrinopathy
Animal model
Rat
Phosphonic acids
Phosphoric monoester hydrolases
Non peptide compound
Esterases
Phosphorus Organic compounds
Geminal compound
Structure activity relation
Bromine Organic compounds
Chemical synthesis
Enzyme
Rodentia
Oral administration
Enzyme inhibitor
Bioavailability
In vitro
In vivo
Vertebrata
Mammalia
Hydrolases
Benzenic compound
Fluorine Organic compounds
Pharmacokinetics
Protein-tyrosine-phosphatase
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Summary: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).
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2003.11.048