Discovery of a Potent and Selective Free Fatty Acid Receptor 1 Agonist with Low Lipophilicity and High Oral Bioavailability

Christiansen, Elisabeth; Due-Hansen, Maria E.; Urban, Christian; Grundmann, Manuel; Schmidt, Johannes; Hansen, Steffen V. F.; Hudson, Brian D.; Zaïbi, Mohamed S.; Markussen, Stine B; Hagesæther, Ellen; Milligan, Graeme; Cawthorne, Michael A.; Kostenis, Evi; Kassack, Matthias U.; Ulven, Trond

doi:10.1021/jm301470a

Cited by 49 publications

(47 citation statements)

References 48 publications

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“…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

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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

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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

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“…The optimal nitrile TUG‐488 (hEC 50 = 20 nM) revealed drastically improved stability toward HLM (81%) and lipophilicity (log D 7.4 = 1.28). However, the PK profile of TUG‐488 is still unsatisfactory, despite a threefold higher plasma exposure compared with TUG‐424 . Interestingly, the corresponding 2‐fluoro analog TUG‐770 indicated a pronounced increase in agonistic activity (hEC 50 = 6 nM) and a superior PK profile (CL total = 3.1 mL/min/kg, AUC iv = 809 μg·min/mL, t 1/2, iv = 119 min) compared with TUG‐488 (CL total = 14 mL/min/kg, AUC iv = 174 μg·min/mL, t 1/2, iv = 17 min).…”

Section: Synthetic Ffar1 Agonists Based On Different Strategiesmentioning

confidence: 99%

Free Fatty Acid Receptor 1 (FFAR1) as an Emerging Therapeutic Target for Type 2 Diabetes Mellitus: Recent Progress and Prevailing Challenges

Xue

Huang

et al. 2017

Medicinal Research Reviews

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The free fatty acid receptor 1 (FFAR1/GPR40) amplifies glucose-dependent insulin secretion; therefore, it has attracted widespread attention as a promising antidiabetic target. Current clinical proof of concept also indicates that FFAR1 agonists achieve the initially therapeutic endpoint for the treatment of type 2 diabetes mellitus (T2DM) without the hypoglycemic risk. Thus, many pharmaceutical companies and academic institutes are competing to develop FFAR1 agonists. However, several candidates have been discontinued in clinical trials, often without reporting the underlying reasons. Herein, we review the challenges and corresponding strategies chosen by different medicinal chemistry teams to improve the physicochemical properties, potency, pharmacokinetics, and safety profiles of FFAR1 agonists, with a brief introduction to the biology and pharmacology of related targets.

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“…In an academic context, the University of Southern Denmark have developed 4-(benzylamine)hydrocinnamic acid FFA1 agonists such as TUG-469 (47, 48) and 4-alkyne hydrocinnamic acid FFA1 agonists, including TUG-424 and TUG-770 (49–51) (Table 1). Within these programs, several strategies have been followed to reduce compound lipophilicity (48, 52, 53). Consequently, TUG-770 (Figure 2) has recently been described as a highly potent FFA1 agonist with favorable physicochemical and pharmacokinetic properties, improving glucose tolerance in diet-induced obese mice.…”

Section: Ffa1 Agonists: Ongoing Ffa1 Drug Programs and Future Challengesmentioning

confidence: 99%

Treatment of Type 2 Diabetes by Free Fatty Acid Receptor Agonists

et al. 2014

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Dietary free fatty acids (FFAs), such as ω-3 fatty acids, regulate metabolic and anti-inflammatory processes, with many of these effects attributed to FFAs interacting with a family of G protein-coupled receptors. Selective synthetic ligands for free fatty acid receptors (FFA1-4) have consequently been developed as potential treatments for type 2 diabetes (T2D). In particular, clinical studies show that Fasiglifam, an agonist of the long-chain FFA receptor, FFA1, improved glycemic control and reduced HbA1c levels in T2D patients, with a reduced risk of hypoglycemia. However, this ligand was removed from clinical trials due to potential liver toxicity and determining if this is a target or a ligand-specific feature is now of major importance. Pre-clinical studies also show that FFA4 agonism increases insulin sensitivity, induces weight loss, and reduces inflammation and the metabolic and anti-inflammatory effects of short chain fatty acids (SCFAs) are linked with FFA2 and FFA3 activation. In this review, we therefore show that FFA receptor agonism is a potential clinical target for T2D treatment and discuss ongoing drug development programs within industry and academia aimed at improving the safety and effectiveness of these potential treatments.

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Discovery of a Potent and Selective Free Fatty Acid Receptor 1 Agonist with Low Lipophilicity and High Oral Bioavailability

Cited by 49 publications

References 48 publications

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

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

Free Fatty Acid Receptor 1 (FFAR1) as an Emerging Therapeutic Target for Type 2 Diabetes Mellitus: Recent Progress and Prevailing Challenges

Treatment of Type 2 Diabetes by Free Fatty Acid Receptor Agonists

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