Design, Synthesis And SAR Evaluation Of New DPP-Ⅳ Inhibitors

Diabetes is one of the fastest growing health concerns worldwide. The total number of people with all types of diabetes is projected to rise from approximately 171 million in the year 2000 to 366 million in 2030, primarily due to population growth, aging, urbanization, and increasing prevalence of obesity and physical inactivity. Type 2 diabetes mellitus (T2DM) is a complex multifactorial disease affecting the length and quality of life of an affected individual. It is estimated that, in 2006, some 194 million people worldwide, or 5.1% of the adult population, had diabetes. T2DM is a progressive disorder accompanied by deterioration inβcell function and insulin resistance. Remaining untreated, chronic hyperglycemia is directly correlated with the occurrence of microvascular complications which can ultimately lead to renal failure, blindness, and loss of life. Currently, the oral monotherapy or combination therapeutics with other drugs are main methods to aid in the control of diabetes by using all kinds of available antidiabetic agents in the clinical anti-diabetes therapy. However, current pharmacological treatments of type 2 diabetes have many limitations. For example Sulfonylureas are associated with hypoglycaemia and weight gain. The biguanides can lead to gastrointestinal side effects. One of the main side effects of Thiazolidinediones (TZDs) is water retention, leading to oedema and weight gain. Although insulin treatment is very effective in achieving glycaemic control, its use is invariably associated with weight gain due to increased body fat mass, in particular abdominal obesity. Apparently, There is clearly a need for newer pharmacological agents which are with good potency and low toxicity.Among numerous possible targets, DPP-IV inhibition appears to be one of the most promising. Dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5) is a ubiquitous yet highly specific serine protease that cleaves N-terminal dipeptides from polypeptides with L-proline or L-alanine at the penultimate position. DPP-IV widely expresses in many tissues such as the liver, lung, kidney, intestinal brush border membranes, lymphocytes, and endothelial cells. This enzyme regulates the levels of several gastrointestinal hormones in the body including Glucagon-like peptide (GLP-1) and Glucose dependent insulinotropic polypeptide (GIP). GLP-1 has several beneficial effects for blood glucose control such as stimulation of insulin secretion, inhibition of glucagon secretion, and delaying gastric emptying. However GLP-1 is rapidly degraded by DPP-IV. Although GLP-1 is secreted as GLP-1 (7-36) amide from the small and large intestines in response to dietary signals, it is rapidly truncated to GLP-1 (9-36) by cleavage of the N-terminal dipeptide residues. The truncated metabolite has antagonist activity against the GLP-1 receptor both in vitro and in vivo. So, inhibition of DPP-IV has been shown to be effective at sustaining circulating levels of GLP-1 (7-36) and therefore offers a new therapeutic approach for the treatment of type 2 diabetes.Several compound classes of DPP-IV inhibitors are known, the most prominent being cyanopyrrolidines, noncyano-pyrrolidines and -thiazolines, xanthine-derived compounds andβ-phenethylamines. We made use of arylmethylamine-based compounds to construct the 3D-QSAR, Pharmacophore and Docking models. Moreover, the ligand-based and structure-based virtual screening were used to search for the new scaffold DPP-IV inhibitors. The compounds got were evaluated by the Pharmacophore and Docking models. Comparing the scaffold between the virtual screening compounds and DPP-IV inhibitors recently reported, we synthetized 3 series of compounds.3 compounds compared to sitagliptin showed good DPP-IV inhibition in vitro and controled the blood sugar in vivo well.