formylchromone and Diabetes-Mellitus--Type-2

Diabetes mellitus is a systemic disease responsible for morbidity in the western world and is gradually becoming prevalent in developing countries too. The prevalence of diabetes is rapidly increasing in industrialized countries and type 2 diabetes accounts for 90% of the disease. Insulin resistance is a major pathophysiological factor in the development of type 2 diabetes, occurring mainly in muscle, adipose tissues, and liver leading to reduced glucose uptake and utilization and increased glucose production. The prevalence and rising incidence of diabetes emphasized the need to explore new molecular targets and strategies to develop novel antihyperglycemic agents. Protein Tyrosine Phosphatase 1B (PTP 1B) has recently emerged as a promising molecular level legitimate therapeutic target in the effective management of type 2 diabetes. PTP 1B, a cytosolic nonreceptor PTPase, has been implicated as a negative regulator of insulin signal transduction. Therefore, PTP 1B inhibitors would increase insulin sensitivity by blocking the PTP 1B-mediated negative insulin signaling pathway and might be an attractive target for type 2 diabetes mellitus and obesity. With X-ray crystallography and NMR-based fragment screening, the binding interactions of several classes of inhibitors have been elucidated, which could help the design of future PTP 1B inhibitors. The drug discovery research in PTP 1B is a challenging area to work with and many pharmaceutical organizations and academic research laboratories are focusing their research toward the development of potential PTP 1B inhibitors which would prove to be a milestone for the management of diabetes.

Topics: Acetophenones; Amino Acid Sequence; Animals; Benzoates; Benzofurans; Biphenyl Compounds; Blood Glucose; Catalytic Domain; Catechols; Chromones; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Fluorides; Humans; Insulin; Insulin Resistance; Insulin Secretion; Janus Kinase 2; Models, Molecular; Naphthoquinones; Peptidomimetics; Phosphates; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Pyridazines; Receptor, Insulin; Signal Transduction; STAT3 Transcription Factor; Thiazoles; Thiazolidinediones; Thiophenes; Vanadium Compounds

Protein tyrosine phosphatase 1B (PTP 1B), a negative regulator of insulin receptor signaling system, has emerged as a highly validated, attractive target for the treatment of non-insulin dependent diabetes mellitus (NIDDM) and obesity. As a result there is a growing interest in the development of potent and specific inhibitors for this enzyme. This quantitative structure-activity relationship (QSAR) study for a series of formylchromone derivatives as PTP lB inhibitors was performed using genetic function approximation (GFA) technique. The QSAR models were developed using a training set of 29 compounds and the predictive ability of the QSAR model was evaluated against a test set of 7 compounds. The internal and external consistency of the final QSAR model was 0.766 and 0.785. The statistical quality of QSAR models was assessed by statistical parameters r2, r2 (crossvalidated r2), r2pred (predictive r2) and lack of fit (LOF) measure. The results indicate that PTP lB inhibitory activity of the formylchromone derivatives is strongly dependent on electronic, thermodynamic and shape related parameters.

Topics: Chemistry, Pharmaceutical; Chromones; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Humans; In Vitro Techniques; Models, Chemical; Models, Molecular; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases; Quantitative Structure-Activity Relationship