gw-7647 and Diabetes-Mellitus--Type-2

The free fatty acid receptor 1 (FFA1) and peroxisome proliferator-activated receptors (PPARs) have attracted interest as potent targets for the treatment of metabolic syndrome such as type 2 diabetes. Based on the hypothesis that the dual agonists of PPARs and FFA1 would act as insulin sensitizers and secretagogues by simultaneous activation of PPARs and FFA1, we developed the design strategy to obtain dual PPARs/FFA1 agonist by hybrid FFA1 agonist 1 with PPARδ agonist 2 in consideration of their structural similarity. As expected, systematic exploration of structure-activity relationship and molecular modeling, results in the discovery of lead compound 15, a pan agonist with relative balanced activities between FFA1, PPARγ and PPARδ. The dose-response relationship studies suggested that the pan agonist 15 suppressed the excursion of blood glucose levels in a dose-dependent manner. During a 5-days treatment in ob/ob mice, the pan agonist 15 (100 mg/kg) revealed sustained hypoglycemic effect, even proximity to the most advanced FFA1 agonist (TAK-875, 40 mg/kg), which might be attributed to its pan PPARs/FFA1 activities to simultaneous regulate the mechanism of insulin secretion and resistance. These positive results suggest that the dual PPARs/FFA1 agonists such as lead compound 15 might be novel therapeutic strategy to modulate the complex pathological mechanisms of type 2 diabetes.

Topics: Animals; CHO Cells; Cricetulus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Design; Glucose Tolerance Test; HEK293 Cells; Hep G2 Cells; Humans; Hypoglycemic Agents; Male; Mice; Mice, Inbred ICR; Mice, Obese; Models, Molecular; Molecular Structure; PPAR delta; PPAR gamma; Receptors, G-Protein-Coupled; Structure-Activity Relationship

Metabolic syndrome (MetS) is a multifactorial disease cluster that consists of dyslipidemia, cardiovascular disease, type 2 diabetes mellitus, and obesity. MetS patients are strongly exposed to polypharmacy; however, the number of pharmacological compounds required for MetS treatment can be reduced by the application of multitarget compounds. This study describes the design of dual-target ligands that target soluble epoxide hydrolase (sEH) and the peroxisome proliferator-activated receptor type γ (PPARγ). Simultaneous modulation of sEH and PPARγ can improve diabetic conditions and hypertension at once. N-Benzylbenzamide derivatives were determined to fit a merged sEH/PPARγ pharmacophore, and structure-activity relationship studies were performed on both targets, resulting in a submicromolar (sEH IC50 = 0.3 μM/PPARγ EC50 = 0.3 μM) modulator 14c. In vitro and in vivo evaluations revealed good ADME properties qualifying 14c as a pharmacological tool compound for long-term animal models of MetS.

Topics: 3T3 Cells; Administration, Oral; Animals; Benzamides; Chlorocebus aethiops; COS Cells; Diabetes Mellitus, Type 2; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Epoxide Hydrolases; Humans; Hypertension; In Vitro Techniques; Metabolic Syndrome; Mice; Microsomes, Liver; PPAR gamma; Rats; Structure-Activity Relationship