Discovery of novel PTP1B inhibitors with antihyperglycemic activity.
OBJECTIVE
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 IRbeta 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).


CONCLUSIONS
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.
Liu
Zhang
Z
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Chai
Qian
Q
Li
Yuan-yuan
YY
Shen
Qiang
Q
Ma
Lan-ping
LP
Zhang
Li-na
LN
Wang
Xin
X
Sheng
Li
L
Li
Jing-ya
JY
Li
Jia
J
Shen
Jing-kang
JK
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors*; D053778:Thiazolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D053778:Thiazolidines; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1