Discovery of 5-aryloxy-2,4-thiazolidinediones as potent GPR40 agonists.
ABSTRACT Systematic structure-activity relationship (SAR) studies of a screening lead led to the discovery of a series of thiazolidinediones (TZDs) as potent GPR40 agonists. Among them, compound C demonstrated an acute mechanism-based glucose-lowering in an intraperitoneal glucose tolerance test (IPGTT) in lean mice, while no effects were observed in GPR40 knock-out mice.
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ABSTRACT: 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.Journal of molecular graphics & modelling 02/2011; 29(6):818-25. DOI:10.1016/j.jmgm.2011.01.006
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ABSTRACT: Discovery of G protein coupled receptors for long chain free fatty acids (FFAs), FFA1 (GPR40) and GPR120, has expanded our understanding of these nutrients as signaling molecules. These receptors have emerged as important sensors for FFA levels in the circulation or the gut lumen, based on evidence from in vitro and rodent models, and an increasing number of human studies. Here we consider their promise as therapeutic targets for metabolic disease, including type 2 diabetes and obesity. FFA1 directly mediates acute FFA-induced glucose-stimulated insulin secretion in pancreatic beta-cells, while GPR120 and FFA1 trigger release of incretins from intestinal endocrine cells, and so indirectly enhance insulin secretion and promote satiety. GPR120 signaling in adipocytes and macrophages also results in insulin sensitizing and beneficial anti-inflammatory effects. Drug discovery has focused on agonists to replicate acute benefits of FFA receptor signaling, with promising early results for FFA1 agonists in man. Controversy surrounding chronic effects of FFA1 on beta-cells illustrates that long term benefits of antagonists also need exploring. It has proved challenging to generate highly selective potent ligands for FFA1 or GPR120 subtypes, given that both receptors have hydrophobic orthosteric binding sites, which are not completely defined and have modest ligand affinity. Structure activity relationships are also reliant on functional read outs, in the absence of robust binding assays to provide direct affinity estimates. Nevertheless synthetic ligands have already helped dissect specific contributions of FFA1 and GPR120 signaling from the many possible cellular effects of FFAs. Approaches including use of fluorescent ligand binding assays, and targeting allosteric receptor sites, may improve further pre-clinical ligand development at these receptors, to exploit their unique potential to target multiple facets of diabetes.Frontiers in Endocrinology 01/2011; 2:112. DOI:10.3389/fendo.2011.00112