Discovery of 5-aryloxy-2,4-thiazolidinediones as potent GPR40 agonists

Merck Research Laboratories, Rahway, NJ 07065, USA.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.42). 02/2010; 20(3):1298-301. DOI: 10.1016/j.bmcl.2009.10.052
Source: PubMed


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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    • "In part the screening for novel FFA1 compounds was aided by the early discovery that certain thiazolidinedione (TZD) PPARγ ligands, such as rosiglitazone, were also agonists at FFA GPCRs (Kotarsky et al., 2003; Tan et al., 2008; Smith et al., 2009). Some of the novel FFA1 agonists (e.g., Tan et al., 2008; Zhou et al., 2010) are thus structurally based on the TZD backbone, while others arose from conformational restriction of the aliphatic FFA carbon backbone (e.g., Christiansen et al., 2008). Recent studies have also explored ways to improve the pharmacokinetic properties of both FFA1 agonist (Christiansen et al., 2011) and antagonist series (Humphries et al., 2009). "
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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.
    Full-text · Article · Nov 2011 · Frontiers in Endocrinology
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    • "65 As well as inhibiting PI3K, thiazolidinedione derivatives are clinically used PPARγ agonists (pioglitazone, rosiglitazone) and aldose reductase inhibitors (epalrestat), and have research applications as antibacterial, antimalarial, anti-inflammatory, antiviral, herbicidal, insecticidal, antifungal, anticancer, anthelmintic agents, and for the treatment of Alzheimer’s disease, central nervous systems (CNS) disorders, diabetes, cardiovascular, cystic fibrosis and thrombocytopenia.63, 66 They bind to targets as diverse as G protein-coupled receptor 40 (GPR40),67 protein tyrosine phosphatase 3 (PRL-3),68 cyclooxygenase 2 (COX-2),69 the peptidoglycan biosynthesis enzymes, MurB, MurC and MurG,63 B cell lymphoma-2 (Bcl-2),70 phosphodiesterase 4 (PDE4),71 fungal protein mannosyl transferase 1 (PMT1),72 tumor necrosis factor alpha (TNF-α),73 hepatitis C virus nonstructural protein 3 (HCV NS3) and NS5b polymerase (HCV NS5b),74, 75 cytosolic phospholipase A2α (cPLA2α),76 proto-oncogene serine/threonine protein kinase (Pim-1),77 cyclin-dependent kinase 2 (CDK2),54 HIV-1 integrase,78 serotonin N-acetyltransferase (AANAT),79 and glycogen synthase kinase-3β (GSK-3β).80 Several of the most potent compounds identified here have also been picked up in other screening campaigns, offering a cautionary note to the possibility of off-target effects. "
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    ABSTRACT: A series of synthesized and commercially available compounds were assessed against PI3Kα for in vitro inhibitory activity and the results compared to binding calculated in silico. Using published crystal structures of PI3Kγ and PI3Kδ co-crystallized with inhibitors as a template, docking was able to identify the majority of potent inhibitors from a decoy set of 1000 compounds. On the other hand, PI3Kα in the apo-form, modeled by induced fit docking, or built as a homology model gave only poor results. A PI3Kα homology model derived from a ligand-bound PI3Kδ crystal structure was developed that has a good ability to identify active compounds. The docking results identified binding poses for active compounds that differ from those identified to date and can contribute to our understanding of structure–activity relationships for PI3K inhibitors.
    Full-text · Article · Mar 2011 · ChemMedChem
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    • "Drug discovery endeavors have already discovered many GPR40 synthetic ligands [7] [8] [9] [10] [11] and some of these compounds are at various stages of development. Recently, a novel series of agonists originated from 3-(4-{N-alkylamino}phenyl) propanoic acid was described by GlaxoSmithKline, where compound GW9508 appears to be the preferred one (EC 50 = 64.6 nM) [8] [9]. "
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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.
    Full-text · Article · Feb 2011 · Journal of molecular graphics & modelling
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