Design, synthesis and insulin-sensitising effects of novel PTP1B inhibitors

Fifteen novel sulfathiazole-related compounds were designed as PTP1B inhibitors based on a previously reported allosteric inhibitor (1) of PTP1B. These compounds were synthesized and evaluated against human recombinant PTP1B. Six compounds (3, 4, 8 and 14–16) exhibited significant inhibitory activit...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2013-04, Vol.23 (8), p.2313-2318
Main Authors: Tang, Yan-Bo, Lu, Dianyun, Chen, Zheng, Hu, Chun, Yang, Ying, Tian, Jin-Ying, Ye, Fei, Wu, Li, Zhang, Zhong-Yin, Xiao, Zhiyan
Format: Article
Language:English
Subjects:
Animals
chemistry
Disease Models, Animal
Drug Design
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Humans
In vivo insulin-sensitising effects
inhibitory concentration 50
insulin
Insulin - metabolism
Insulin Resistance
Mice
Models, Molecular
Molecular Conformation
Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors
Protein Tyrosine Phosphatase, Non-Receptor Type 1 - chemistry
PTP1B inhibitors
Recombinant Proteins - chemistry
Selectivity
Structure-Activity Relationship
Sulfathiazoles - chemical synthesis
Sulfathiazoles - chemistry
Sulfathiazoles - pharmacology
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Summary:Fifteen novel sulfathiazole-related compounds were designed as PTP1B inhibitors based on a previously reported allosteric inhibitor (1) of PTP1B. These compounds were synthesized and evaluated against human recombinant PTP1B. Six compounds (3, 4, 8 and 14–16) exhibited significant inhibitory activity against PTP1B. The most active compound (16) showed IC50 value of 3.2μM and kinetic analysis indicated that it is a non-competitive inhibitor of PTP1B. Furthermore, compound 16 demonstrated excellent selectivity to PTP1B over other PTPs. It also displayed in vivo insulin sensitizing effect in the insulin resistant mice.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2013.02.073