Novel benzamido derivatives as PTP1B inhibitors with anti-hyperglycemic and lipid-lowering efficacy

Based on a non-competitive and selective PTP1B inhibitor reported by us previously, thirty-nine benzamido derivatives were designed and synthesized as novel PTP1B inhibitors. Among them, twelve compounds exhibited IC values at micromolar level against human recombinant PTP1B, and most of them exhibited significant selectivity to PTP1B over TC-PTP and CD45. Further evaluation of the most potent compound on high-fat diet (HFD)-induced insulin-resistant (IR) obese mice indicated that could modulate glucose metabolism and ameliorate dyslipidemia simultaneously.

The effects of compound CX09040 on the inhibition of PTP1B and protection of pancreatic β cells / 药学学报

To investigate the effects of 2-(4-methoxycarbonyl-2-tetradecyloxyphenyl)carbamoylbenzoic acid (CX09040) on protecting pancreatic β cells, the β cell dysfunction model mice were induced by injection of alloxan into the caudal vein of ICR mice, and were treated with compound CX09040. Liraglutide was used as the positive control drug. The amount and the size of islets observed in pathological sections were calculated to evaluate the β cell mass; the glucose stimulated insulin secretion (GSIS) test was applied to estimate the β cell secretary function; the oral glucose tolerance test (OGTT) was taken to observe the glucose metabolism in mice; the expressions of protein in pancreas were detected by Western blotting. The effects on the target protein tyrosine phosphatase 1B (PTP1B) were assessed by the PTP1B activities of both recombinant protein and the intracellular enzyme, and by the PTP1B expression in the pancreas of mice, separately. As the results, with the treatment of CX09040 in alloxan-induced β cell dysfunction mice, the islet amount (P<0.05) and size (P<0.05) increased significantly, the changes of serum insulin in GSIS (P<0.01) and the values of acute insulin response (AIR, P<0.01) were enhanced, compared to those in model group; the impaired glucose tolerance was also ameliorated by CX09040 with the decrease of the values of area under curve (AUC, P<0.01). The activation of the signaling pathways related to β cell proliferation was enhanced by increasing the levels of p-Akt/Akt (P<0.01), p-FoxO1/FoxOl (P<0.001) and PDX-1 (P<0.01). The effects of CX09040 on PTP1B were observed by inhibiting the recombinant hPTP1B activity with IC50 value of 2.78x 10(-7) mol.L-1, reducing the intracellular PTP1B activity of 72.8% (P<0.001), suppressing the PTP1B expression (P<0.001) and up-regulating p-IRβ/IRβ (P<0.01) in pancreas of the β cell dysfunction mice, separately. In conclusion, compound CX09040 showed significant protection effects against the dysfunction of β cell of mice by enlarging the pancreatic β cell mass and increasing the glucose-induced insulin secretion; its major mechanism may be the inhibition on target PTP1B and the succedent up-regulation of β cell proliferation.

SAR of benzoyl sulfathiazole derivatives as PTP1B inhibitors / 药学学报

Protein tyrosine phosphatase (PTP) 1B is a potential target for the treatment of diabetes and obesity. We have previously identified the benzoyl sulfathiazole derivative II as a non-competitive PTP1B inhibitor with in vivo insulin sensitizing effects. Preliminary SAR study on this compound series has been carried out herein, and thirteen new compounds have been designed and synthesized. Among them, compound 10 exhibited potent inhibition against human recombinant PTP1B with the IC50 value of 3.97 micromol x L(-1), and is comparable to that of compound II.

Investigation of a compound, compatibility of Rhodiola crenulata, Cordyceps militaris, and Rheum palmatum, on metabolic syndrome treatment I--improving insulin resistance / 中国中药杂志

To investigate the effects of a compound (FF16), compatibility of Rhodiola crenulata, Cordyceps militaris, and Rheum palmatum, on insulin resistance. The results showed that FF16 significantly improved the insulin sensitivity through decreasing AUC values in insulin tolerance tests by 24.1%, 38.5%; reducing the levels of serum insulin by 46.0%, 30.4%, of HOMA-IR by 52.4%, 81.2%; and reversing the lower GIR values by 119.3%, 202.4% in IRF mice and KKAy mice, respectively. In addition, in KKAy mice, the value of whole body insulin sensitivity index (ISWBI) was enhanced by 1.0 times, the abilities of the insulin-induced glucose uptake in liver, adipose and skeletal muscle were enhanced by 1.5, 2.8 and 2.2 times, respectively, in FF16-treated mice comparing with those in model mice. The recombinant human protein tyrosine phosphatase 1B (PTP1B) activity was inhibited by FF16 in vitro with the IC50 value of 0.225 mg x L(-1). The increased PTP1B expression in the liver was also reversed by 45.8% with the administration of FF16 in IRF mice. In conclusion, FF16 could improve insulin resistance by inhibiting the activity of PTP1B.

Design, synthesis and evaluation of malonic acid-based PTP1B inhibitors / 药学学报

Protein tyrosine phosphatase (PTP) 1B is a potential target for the treatment of diabetes and obesity. Phosphotyrosine (pTyr) is the substrate for PTP1B dephosphorylation. Malonic acid moiety was used herein as a mimic of the phosphate group in pTyr, and novel malonic acid derivatives 1-7 were designed, synthesized and evaluated as PTP1B inhibitors. Results from enzymatic assays indicated that compounds 3 and 4 exhibited potent inhibition against human recombinant PTP1B with IC50 values of 7.66 and 1.88 micromol x L(-1), respectively.

Preliminary identification of the mutant human embryonic lung fibroblast Z-HL_(16)C cell strain / 基础医学与临床

Objective To study the characteristics of Z-HL_(16)C cell strain mutated from the human embryonic lung fibroblasts(HL).Methods Morphology observation,chromosome cytogenetics,tumorigenesis in nude mice,and the sensitivity to virus were examined.Results As a transformed cell strain,the Z-HL_(16)C showed polygon shapes liking epithelium;the number of chromosome was sub-triploid or hyper-triploid,and the structures of 30%～40% chromosomes were abnormal.The incidence of its inoculation in nude mice was 100%,and the pathological studies proved its tumorigenesis.The cytopathic effects of many kinds of viruses were observed in Z-HL_(16)C cell strain.Conclusion The Z-HL_(16)C is one of the cancer cell strains transformed from HL cells.