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The free fatty acid receptor 1 (FFA1 or GPR40) and peroxisome proliferator-activated receptor δ (PPARδ) have attracted a lot of attention due to their role in promoting insulin secretion and sensibility, respectively, which are two major features of diabetes. Therefore, the dual FFA1/PPARδ agonists would increase insulin secretion and sensibility by FFA1 and PPARδ activation. In this study, we hybrid FFA1 agonist AM-4668 with PPARδ agonist GW501516, leading to the identification of orally bioavailable dual agonist 32, which revealed high selectivity over other PPARs. Moreover, compound 32 exhibited good pharmacokinetic profiles with high plasma concentration, sustained half-life and low clearance in vivo. During the hypoglycemic test, a dual agonist 32 enhanced the tolerance of ob/ob mice for glucose loading in a dose-dependent manner. Our results suggest that dual FFA1/PPARδ agonist could be a valuable therapy for type 2 diabetes.
This article was published in the following journal.
Name: European journal of medicinal chemistry
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....
We previously published on the design and synthesis of novel, potent and selective PPARα antagonists suitable for either i.p. or oral in vivo administration for the potential treatment of cancer. Des...
FFA1 (free fatty acid receptor 1) has emerged as an attractive antidiabetic target due to its role in mediating the enhancement of glucose-stimulated insulin secretion in pancreatic β cells with a lo...
A new series of derivatives of the PPARα/γ dual agonist 1 allowed to identify the ligand (S)-6 as a potent partial agonist of both PPARα and γ subtypes. X-ray studies in PPARγ revealed two differ...
Free fatty acid 1 (FFA1/GPR40) has attracted extensive attention as a novel target for the treatment of type 2 diabetes for its role in the enhancement of insulin secretion with glucose dependency. Ai...
Agonistic activation of fat metabolite responsive G-protein-coupled receptors (GPCR) has been linked to improved glucose metabolism through increased glucose-stimulated-insulin-secreting (...
This research program is in keeping with the chemistry/biology/clinical interface and gathers 4 teams with complementary expertise in these respective fields. It will allow deciphering the...
The objective of the study is to compare PPAR activities (increase of adiponectin level) between MICARDIS and amlodipine after 6 weeks of treatment in hypertensive patients with metabolic ...
To test the hypothesis that stimulation of PPAR-γ receptors has a therapeutic role in the treatment of asthma.
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One of the PPAR nuclear transcription factors.
Experience-based techniques for problem-solving, learning, and discovery that find a solution which is not guaranteed to be optimal, but sufficient for a given set of goals.
A process that searches for hidden and important connections among information embedded in published literature.
The co-existence of a substance abuse disorder with a psychiatric disorder. The diagnostic principle is based on the fact that it has been found often that chemically dependent patients also have psychiatric problems of various degrees of severity.
A dual specificity phosphatase subtype that plays a role in intracellular signal transduction by inactivating MITOGEN-ACTIVATED PROTEIN KINASES. It has specificity for EXTRACELLULAR SIGNAL-REGULATED MAP KINASES.
Diabetes is a lifelong condition that causes a person's blood sugar level to become too high. The two main types of diabetes are: type 1 diabetes type 2 diabetes In the UK, diabetes affects approximately 2.9 million people. There are a...
Endocrine disorders are grouped into two categories: hormone imbalance - when a gland produces too much or too little of an endocrine hormone development of lesions (such as nodules or tumors) in the endocrine system, which may or may not affect...
Nephrology - kidney function
Nephrology is a specialty of medicine and pediatrics that concerns itself with the study of normal kidney function, kidney problems, the treatment of kidney problems and renal replacement therapy (dialysis and kidney transplantation). Systemic conditions...