Discovery of novel PTP1B inhibitors with antihyperglycemic activity

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 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).

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.

Figure 1

Effects of 7Fb and 7Fc on tyrosine phosphorylation of IRβ in CHO/hIR cells. The tyrosine phosphorylation level were determined by specific antibody of phosphorylated IR-Tyr^1162/1163 with or without treatment, the β-actin represents the sample amount loaded. BL1 and BL2, 0.2% DMSO; PC, 1 mmol/L orthvandate; and the compound centratration unit is μmol/L.

Figure 2

Glucose tolerance capacity improved by 7Fb. Diabetic BKS db/db mice were treated orally with 7Fb or metformin, the diabetic and wild-type mice were gavaged with 5% methylcellulose (MC) as control group for 4 weeks. The glucose tolerance test (2 g/kg glucose ip) was performed after 6 h fasting and blood glucose level at the above time-points were recorded. Differences between groups were analyzed by Student's t-test. ^bP<0.05, ^cP<0.01 vs BKS-Veh.

Scheme 1

Reagents and conditions: a) 4-Bromo benzaldehyde, MeOH, 50 °C, 6 h; b) Ar-B(OH)₂ (4A–4D), 1 mol% Pd(OAc)₂, K₂CO₃, MeOH, 80 °C, 8 h; c) Cleavage reagents, AcOH, NaOAc, 120 °C, 12 h; d) Rb-Br (6A–6I), K₂CO₃, CH₃CN, 80 °C, 12 h.