Design, Synthesis And SAR Analysis Of Novel GLP-1 Secretagogues And GPR119 Agonists

Diabetes is defined as a chronic metabolic disorder characterized by high blood glucose level. This disease has become a worldwide burden to patients and society due to its high morbidity and mortality along with extraordinarily high medical expenses. However, no effective agent has been discovered to completely cure diabetes and persistent glycaemic control is a key approach for the disease management. Despite a variety of treatments existing, many patients are unable to achieve their target plasma glucose levels. Furthermore, current therapies have efficacy limitations or potential safety risks over a long-term treatment. Recently, glucagon-like peptide-1 (GLP-1) has been emerged as a promising target for diabetes treatment owing to its favorable effects on glucose homeostasis and β-cell preservation. GLP-1 analogs and DPP4 inhibitors, which inhibiting the degradation of endogenous GLP-1, are widely used in clinical therapy for diabetes. G protein-coupled receptors 119 (GPR119), predominantly expressed in pancreatic β cell and intestinal L-cell, is involved in the secretion of insulin and GLP-1. Preclinical and clinical studies indicate that orally available, potent, selective GPR119 agonists are potential novel candidates for diabetes treatment.Our initial work led to the discovery of WB403, which decreased the blood glucose level efficiently in cell-based and animial models evaluations by promoting the release of GLP-1, while its exact target has not been identified. In order to improve the activity of WB403 and explore its possible mechanism, WB403 was selected as a lead compound for further optimization. Additionally, another part of this subject was to combine the pharmacophore scaffold with the common fragments of GPR119 agonists in similar spatial position to generate a series of agonists target GPR119 with improved physical and chemical activities.The GLP-1 and GPR119 agonistic activities of the synthesized compounds were evaluated via cell-based assays. The results showed that the activities of compounds C5 and C9 were retained with physicochemical properties improved compared with WB403. Another series of GPR119 agonists displayed increased solubilities while the agonistic activities were unappealing.