Synthesis and Evaluation of Barbituric Acid Derivatives as Protein Tyrosine Phosphatase 1B Inhibitors

Abstract

Rapid increase of obesity and diabetes in modern society increases the risk of other complications, such as cardiovascular diseases, blindness, renal failure and even cancer. Orlistat is the only drug approved currently by the US Food and Drug Administration (FDA) for the treatment of obesity. Other drugs previously approved were suspended due to side effects. Sulfonylureas, thiazolidinediones, and meglitinides are available in the market as the drugs for type 2 diabetes mellitus but they are not kept a distance from side effects. Science communities have been focusing attention on the development of novel drugs that are safer and more efficient in treating obesity and diabetes. Protein tyrosine phosphatase1B (PTP1B) is an enzyme closely related with these diseases. PTP1B is a negative regulator of leptin and insulin signaling pathways. Genetic deletion of PTP1B in mice improved both leptin and insulin signaling, resulting in the resistance to diet-induced obesity and the enhancement of insulin sensitivity and glucose tolerance. The enhancement of leptin signaling reduced food intake and increased energy expenditure, resulting in weight loss in mammals. Increased PTP1B expression has also been observed in insulin-resistant states associated with obesity. These results established PTP1B as a target for the treatment of both obesity and type 2 diabetes. The aim of this research is to develop low molecular weight inhibitors of PTP1B which have a good inhibitory potency, selectivity and favorable pharmacokinetics for the development of antidiabetic and antiobesity drugs. Barbituric acid was selected as a scaffold for the derivatization. A series of derivatives containing a single substitutuent were synthesized and their efficacy to inhibit PTP1B activity was determined. The most potent compound II-5e showed IC 50 of 11 µM against PTP1B and 27 µM against VHR. The nature of inhibition by compound II-5e was investigated by steady-state kinetic experiments with PTP1B, VHR and YPTP1. When the mode of inhibition was examined by the Lineweaver-Burk plot analysis of the kinetic experiments, II-5e inhibited PTP1B and YPTP1 noncompetitively and VHR competitively.