Abstract
Aim:
To discover and optimize a series of novel PTP1B inhibitors containing a thiazolidinone-substituted biphenyl scaffold and to further evaluate the inhibitory effects of these compounds in vitro and in vivo.
Methods:
A total of 36 thiazolidinone substituted biphenyl scaffold derivatives were prepared. An in vitro biological evaluation was done by Enzyme-based assay. The in vivo efficacy of 7Fb as an antihyperglycemic agent was evaluated in a BKS db/db diabetic mouse model with a dose of 50 mg·kg-1·d-1 for 4 weeks.
Results:
The in vitro biological evaluation showed that compounds 7Fb and 7Fc could increase the insulin-induced tyrosine phosphorylation of IRβ in CHO/hIR cells. In in vivo experiments, compound 7Fb significantly lowered the postprandial blood glucose, from 29.4±1.2 mmol/L with the vehicle to 24.7±0.6 mmol/L (P<0.01), and the fasting blood glucose from 27.3±1.5 mmol/L with the vehicle to 23.6±1.2 mmol/L (P<0.05).
Conclusion:
A novel series of compounds were discovered to be PTP1B inhibitors. Among them, compound 7Fb significantly lowered the postprandial and fasting glucose levels, and the blood glucose level declined more rapidly than in metformin-treated mice. Thus, 7Fb may be a potential lead compound for developing new agents for the treatment of type II diabetes.
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Acknowledgements
This work was supported by the 863 High-Tech Research and Development Program of China (Grant 2006AA02Z315 and 2008AA02Z105), the National S&T Major Projects “Key New Drug Creation and Manufacturing Program” of China (No 2009ZX09301-001, 2009ZX09302-001 and 2009ZX09501-010) and the Public Service Platform Foundation of Shanghai Ministry of Science and Technology (08DZ2291300 and 09DZ2291200).
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Liu, Z., Chai, Q., Li, Yy. et al. Discovery of novel PTP1B inhibitors with antihyperglycemic activity. Acta Pharmacol Sin 31, 1005–1012 (2010). https://doi.org/10.1038/aps.2010.81
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DOI: https://doi.org/10.1038/aps.2010.81
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