Structure−Activity Study of Dihydrocinnamic Acids and Discovery of the Potent FFA1 (GPR40) Agonist TUG-469

Christiansen, Elisabeth; Due-Hansen, Maria E.; Urban, Christian; Merten, Nicole; Pfleiderer, Michael; Karlsen, Kasper K.; Rasmussen, Sanne S.; Steensgaard, Mette; Hamacher, Alexandra; Schmidt, Johannes; Drewke, Christel; Petersen, Rasmus Koefoed; Kristiansen, Karsten; Ullrich, Susanne; Kostenis, Evi; Kassack, Matthias U.; Ulven, Trond

doi:10.1021/ml100106c

Cited by 57 publications

(78 citation statements)

References 31 publications

(76 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…After 48 h, cells were washed and incubated for 30 min in Krebs-Ringer-bicarbonate buffer (KRB) containing 135 mM NaCl, 3.6 mM KCl, 0.5 mM NaH 2 PO 4 , 2 mM NaHCO 3 , 0.5 mM MgCl 2 , 1.5 mM CaCl 2 , 10 mM HEPES, 2.8 or 20.0 mM glucose, and 0.05% BSA, together with either indomethacin or vehicle. The buffer was replaced with 0.5 ml of fresh KRB containing either vehicle, indomethacin, 10 M TUG469, a synthetic GPR40 agonist (14), or a combination of indomethacin and TUG469. Insulin release was measured after 1 h. MIN6 viability measurements over 48 h were performed using the xCELLigence platform (Roche Applied Science) (15), with indomethacin or vehicle (DMSO) added after 24 h of growth.…”

Section: Methodsmentioning

confidence: 99%

Indomethacin Treatment Prevents High Fat Diet-induced Obesity and Insulin Resistance but Not Glucose Intolerance in C57BL/6J Mice

Fjære

Aune

Røen

et al. 2014

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: Obesity-associated insulin resistance is linked to inflammation. Results: Indomethacin, an anti-inflammatory cyclooxygenase inhibitor, prevented diet-induced obesity, but mice became glucose-intolerant with sustained hepatic glucose output and impaired glucose-stimulated insulin secretion. Conclusion: Inhibition of cyclooxygenase activity alters the metabolic consequences of an obesogenic high fat diet. Significance: Intake of anti-inflammatory cyclooxygenase inhibitors may impair glucose tolerance.

show abstract

Section: Methodsmentioning

confidence: 99%

Indomethacin Treatment Prevents High Fat Diet-induced Obesity and Insulin Resistance but Not Glucose Intolerance in C57BL/6J Mice

Fjære

Aune

Røen

et al. 2014

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…166 Structure−activity relationship exploration around other hits from the process above combined with the simultaneously published GW9508 series resulted in the observations that methyleneoxy was a preferred central linker for small western substituents whereas methyleneamino was preferred for larger compounds and led to the identification of TUG-469 (14, Figure 11) as a potent FFA1 agonist with ability to enhance insulin secretion in a glucose concentration-dependent fashion. 169 The compound was subsequently shown to protect the rodent insulinoma-derived cell line INS-1E against palmitate-induced toxicity through activation of FFA1. 139 Since high lipophilicity was recognized as a potential problem for TUG-469, combination with the hydrophilic 3-mesylpropoxy appendage of the simultaneously disclosed TAK-875 (15) was explored and resulted in TUG-905 (16), an agonist with low lipophilicity and high potency on both human and murine FFA1 orthologs.…”

Section: Synthetic Ligands For Ffa1mentioning

confidence: 99%

Complex Pharmacology of Free Fatty Acid Receptors

et al. 2016

Self Cite

View full text Add to dashboard Cite

G protein-coupled receptors (GPCRs) are historically the most successful family of drug targets. In recent times it has become clear that the pharmacology of these receptors is far more complex than previously imagined. Understanding of the pharmacological regulation of GPCRs now extends beyond simple competitive agonism or antagonism by ligands interacting with the orthosteric binding site of the receptor to incorporate concepts of allosteric agonism, allosteric modulation, signaling bias, constitutive activity, and inverse agonism. Herein, we consider how evolving concepts of GPCR pharmacology have shaped understanding of the complex pharmacology of receptors that recognize and are activated by nonesterified or "free" fatty acids (FFAs). The FFA family of receptors is a recently deorphanized set of GPCRs, the members of which are now receiving substantial interest as novel targets for the treatment of metabolic and inflammatory diseases. Further understanding of the complex pharmacology of these receptors will be critical to unlocking their ultimate therapeutic potential.

show abstract

“…E max is expressed as % of 3. n = 3. d Previously published. [16][17][18][19] e Partial competition that fitted to an allosteric ternary complex model gave pK B = 4.46 and logα = -0.29 (see Figure S2). …”

Section: Characterization Of 4 As An Ffa1 Tracermentioning

confidence: 99%

Development and Characterization of a Potent Free Fatty Acid Receptor 1 (FFA1) Fluorescent Tracer

et al. 2016

Self Cite

View full text Add to dashboard Cite

The free fatty acid receptor 1 (FFA1/GPR40) is a potential target for treatment of type 2 diabetes. Although several potent agonists have been described, there remains a strong need for suitable tracers to interrogate ligand binding to this receptor. We address this by exploring fluorophore-tethering to known potent FFA1 agonists. This led to the development of 4, a high affinity FFA1 tracer with favorable and polarity-dependent fluorescent properties. A close to ideal overlap between the emission spectrum of the NanoLuciferase receptor tag and the excitation spectrum of 4 enabled the establishment of a homogenous BRET-based binding assay suitable for both detailed kinetic studies and high throughput competition binding studies. Using 4 as a tracer demonstrated that the compound acts fully competitively with selected synthetic agonists but not with lauric acid and allowed for the characterization of binding affinities of a diverse selection of known FFA1 agonists, indicating that 4 will be a valuable tool for future studies at FFA1.3

show abstract

Structure−Activity Study of Dihydrocinnamic Acids and Discovery of the Potent FFA1 (GPR40) Agonist TUG-469

Cited by 57 publications

References 31 publications

Indomethacin Treatment Prevents High Fat Diet-induced Obesity and Insulin Resistance but Not Glucose Intolerance in C57BL/6J Mice

Indomethacin Treatment Prevents High Fat Diet-induced Obesity and Insulin Resistance but Not Glucose Intolerance in C57BL/6J Mice

Complex Pharmacology of Free Fatty Acid Receptors

Development and Characterization of a Potent Free Fatty Acid Receptor 1 (FFA1) Fluorescent Tracer

Contact Info

Product

Resources

About