gw9508 and Diabetes-Mellitus--Type-2

Topics: Animals; Benzofurans; Cyclobutanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Methylamines; Molecular Docking Simulation; Phenols; Propionates; Protein Binding; Protein Conformation; Receptors, G-Protein-Coupled; Sulfones

GPR120 is an attractive target for the treatment of type 2 diabetes. In this study, a series of biphenyl derivatives were designed, synthesized by hybrid design. The selected compound 6a exhibited potent GPR120 agonist activity (EC

Topics: Animals; Biphenyl Compounds; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Discovery; Glucose Tolerance Test; Hypoglycemic Agents; Male; Mice, Inbred ICR; Receptors, G-Protein-Coupled; Structure-Activity Relationship

The free fatty acid receptor 1 (FFA1) enhances the glucose-stimulated insulin secretion without the risk of hypoglycemia. However, most of FFA1 agonists have a common biphenyl moiety, leading to a relative deprivation in structure types. Herein, we describe the exploration of non-biphenyl scaffold based on the co-crystal structure of FFA1 to increase additional interactions with the lateral residues, which led to the identification of lead compounds 3 and 9. In induced-fit docking study, compound 3 forms an edge-on interaction with Trp150 by slightly rotating the indole ring of Trp150, and compound 9 has additional hydrogen bond and δ-π interactions with Leu135, which demonstrated the feasibility of our design strategy. Moreover, lead compounds 3 and 9 revealed improved polar surface area compared to GW9508, and have considerable hypoglycemic effects in mice. This structure-based study might inspire us to design more promising FFA1 agonists by increasing additional interactions with the residues outside of binding pocket.

Topics: Animals; Binding Sites; Biphenyl Compounds; Diabetes Mellitus, Type 2; Drug Design; Glucose Tolerance Test; Humans; Hydrogen Bonding; Hypoglycemic Agents; Male; Methylamines; Mice; Mice, Inbred ICR; Molecular Docking Simulation; Propionates; Protein Structure, Tertiary; Receptors, G-Protein-Coupled; Structure-Activity Relationship

The free fatty acid receptor 1 (FFA1/GPR40) has attracted extensive attention as a novel antidiabetic target. Aiming to explore the chemical space of FFA1 agonists, a new series of lead compounds with amide linker were designed and synthesized by combining the scaffolds of NIH screened lead compound 1 and GW9508. Among them, the optimal lead compound 17 exhibited a considerable agonistic activity (45.78%) compared to the NIH screened compound 1 (15.32%). During OGTT in normal mice, the compound 17 revealed a significant glucose-lowering effect (-23.7%) at the dose of 50mg/kg, proximity to the hypoglycemic effect (-27.8%) of Metformin (200mg/kg). In addition, the compound 17 (100mg/kg) also exhibited a significant improvement in glucose tolerance with a 29.1% reduction of glucose AUC

Topics: Amides; Animals; Area Under Curve; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Glucose Tolerance Test; Mice; Structure-Activity Relationship

Activation of G protein-coupled receptor 40 (GPR40) by agonists increases insulin release in isolated islets, whereas it is inconclusive whether GPR40 antagonists decrease blood glucose and increase insulin sensitivity. Although some clinical trials indicated that administration of a GPR40 agonist shows benefits in the regulation of blood glucose homeostasis, the pharmacological mechanisms of this receptor in the improvement of glycemic control remain unclear. Therefore, we used a selective GPR40 agonist, GW-9508, to clarify the role of GPR40 in the regulation of blood glucose. Bolus intraperitoneal injection of GW-9508 in mice showed a slight decrease in blood glucose, with an increase in plasma insulin levels under glucose stimuli. However, long-term treatment with low doses of GW-9508 in high-fat diet-induced (HFD) diabetic mice decreased blood glucose with decreased plasma insulin significantly and improved glucose intolerance and insulin resistance. Using small interfering ribonucleic acid to delete GPR40 in HepG2 cells, we demonstrated that GW-9508 reversed palmitate-induced insulin signaling impairment through a GPR40-dependent pathway. We also found that GW-9508 activates the Akt/GSK-3β pathway to increase glycogen levels in HepG2 cells. Furthermore, administration of GW-9508 decreased the hepatic expression of fetuin-A in HFD mice significantly and regulated high-glucose- or palmitate-induced fetuin-A expression to increase insulin sensitivity through a GPR40/PLC/PKC pathway in HepG2 cells. Taken together, GW-9508 exerts a partial agonist effect to regulate blood glucose through multiple mechanisms. Investigation of chemicals that act on GPR40 might be a new strategy for the treatment of diabetes.

Topics: alpha-2-HS-Glycoprotein; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Diet, High-Fat; Hep G2 Cells; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Liver; Liver Glycogen; Male; Methylamines; Mice; Mice, Inbred C57BL; Propionates; Receptors, G-Protein-Coupled; RNA Interference; Signal Transduction

GPR120 is a receptor of unsaturated long-chain fatty acids reported to mediate GLP-1 secretion, insulin sensitization, anti-inflammatory, and anti-obesity effects and is therefore emerging as a new potential target for treatment of type 2 diabetes and metabolic diseases. Further investigation is however hindered by the lack of suitable receptor modulators. Screening of FFA1 ligands provided a lead with moderate activity on GPR120 and moderate selectivity over FFA1. Optimization led to the discovery of the first potent and selective GPR120 agonist.

Topics: Biphenyl Compounds; Cell Survival; Cinnamates; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; HEK293 Cells; Humans; Magnetic Resonance Spectroscopy; Mass Spectrometry; Molecular Structure; Phenylpropionates; Receptors, G-Protein-Coupled; Structure-Activity Relationship

The free fatty acid receptor 1 (FFA1, also known as GPR40) enhances glucose-stimulated insulin secretion from pancreatic β-cells and is recognized as an interesting new target for treatment of type 2 diabetes. Several series of selective FFA1 agonists are already known. Most of these are derived from free fatty acids (FFAs) or glitazones and are relatively lipophilic. Aiming for the development of potent, selective, and less lipophilic FFA1 agonists, the terminal phenyl of a known compound series was replaced by nitrogen containing heterocycles. This resulted in the identification of 37, a selective FFA1 agonist with potent activity on recombinant human FFA1 receptors and on the rat insulinoma cell line INS-1E, optimal lipophilicity, and excellent in vitro permeability and metabolic stability.

Topics: Animals; Cell Line, Tumor; Cell Membrane Permeability; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; In Vitro Techniques; Insulin; Insulin Secretion; Microsomes, Liver; Models, Molecular; Phenylpropionates; Pyridines; Rats; Receptors, G-Protein-Coupled; Recombinant Proteins; Structure-Activity Relationship

GPR40 is a novel potential target for the treatment of type 2 diabetes. In this work, a two-layered ONIOM based QM/MM approach was employed to study the interactions between GW9508 and GPR40: wild-type, H86F, and H137F mutated systems. The calculated results clearly indicated that His137 is directly involved in ligand recognition through the NH-π interaction with the GW9508. In contrast, His86 is not interacting with the GW9508 in the NH-π interaction. The interaction energies, calculated at the MP2/6-31(d, p) level, were performed to gain more insight into the energetic differences of the wild-type and two mutated systems at the atomistic level. In addition, the obtained pharmacophore model was well consistent with structure-functional requirements for the binding of GPR40 agonists and with per-residue energy decomposition of the ONIOM calculations.

Topics: Binding Sites; Diabetes Mellitus, Type 2; Drug Discovery; Drug Interactions; Methylamines; Models, Biological; Models, Molecular; Molecular Conformation; Mutation; Propionates; Protein Binding; Protein Interaction Mapping; Quantum Theory; Receptors, G-Protein-Coupled

A series of 4-phenethynyldihydrocinnamic acid agonists of the free fatty acid receptor 1 (FFA(1)) has been discovered and explored. The preferred compound 20 (TUG-424, EC(50) = 32 nM) significantly increased glucose-stimulated insulin secretion at 100 nM and may serve to explore the role of FFA(1) in metabolic diseases such as diabetes or obesity.

Topics: Animals; Cinnamates; Crystallography, X-Ray; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Discovery; Glucose; Humans; Insulin; Insulin Secretion; Mice; Models, Molecular; Molecular Structure; Rats; Receptors, G-Protein-Coupled; Stereoisomerism; Structure-Activity Relationship; Time Factors