Synthesis and Evaluation of Barbituric Acid Derivatives as Protein Tyrosine Phosphatase 1B Inhibitors
Date
2012
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Faculty of Chemistry
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.
Description
Keywords
Cardiovascular diseases, Chemical synthesis, Barbituric acid, Protein tyrosine phosphatase