Identification of Fused-Ring Alkanoic Acids with Improved Pharmacokinetic Profiles that Act as G Protein-Coupled Receptor 40/Free Fatty Acid Receptor 1 Agonists

Negoro, Nobuyuki; Sasaki, Shinobu; Ito, Masahiro; Kitamura, Shuji; Tsujihata, Yoshiyuki; Ito, Ryo; Suzuki, Masami; Takeuchi, Koji; Suzuki, Nobuhiro; Miyazaki, Junichi; Santou, Takashi; Odani, Tomoyuki; Kanzaki, Naoyuki; Funami, Miyuki; Tanaka, Toshimasa; Yasuma, Tsuneo; Momose, Yū

doi:10.1021/jm2012968

Cited by 62 publications

(37 citation statements)

References 39 publications

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“…Similarly, an orally active (2,3-dihydro-1-benzofuran-3-yl)acetic acid derivative showed a dose-dependent reduction in glucose levels in Goto-Kakizaki (GK) rats, a type 2 diabetic model with impaired glucose-dependent insulin secretion. Similar results have been found with other agonists (36,41). Finally, Tsujihata et al (46) examined the effect of TAK-875, an orally bioactive GPR40 agonist with an EC 50 for receptor activation of 72 nmol/L.…”

Section: In Vivo Pharmacology Of Gpr40 Agonists In Rodent Modelssupporting

confidence: 91%

Activation of GPR40 as a Therapeutic Target for the Treatment of Type 2 Diabetes

Burant

2013

Diabetes Care

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The stimulation of insulin secretion by glucose can be modulated by multiple nutritive, hormonal, and pharmacological inputs. Fatty acids potentiate insulin secretion through the generation of intracellular signaling molecules and through the activation of cell surface receptors. The G-protein–coupled receptor 40 (GPR40), also known as free fatty acid receptor 1 (we will use GPR40 in this review), has emerged as an important component in the fatty acid augmentation of insulin secretion. By signaling predominantly through Gαq/11, GPR40 increases intracellular calcium and activates phospholipases to generate diacylglycerols resulting in increased insulin secretion. Synthetic small-molecule agonists of GPR40 enhance insulin secretion in a glucose-dependent manner in vitro and in vivo with a mechanism similar to that found with fatty acids. GPR40 agonists have shown efficacy in increasing insulin secretion and lowering blood glucose in rodent models of type 2 diabetes. Recent phase I and phase II clinical trials in humans have shown that the GPR40 agonist TAK-875 reduces fasting and postprandial blood glucose and lowers HbA1c with efficacy equal to that of the sulfonylurea glimepiride without inducing hypoglycemia or evidence of tachyphylaxis. These data suggest that targeting the GPR40 receptor can be a viable therapeutic option for the treatment of type 2 diabetes.

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Section: In Vivo Pharmacology Of Gpr40 Agonists In Rodent Modelssupporting

confidence: 91%

Activation of GPR40 as a Therapeutic Target for the Treatment of Type 2 Diabetes

Burant

2013

Diabetes Care

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“…agonist. [10][11][12][13] BENZOFURAN-3-ACETIC AND NAPHTHAFURAN-ACETIC ACIDS 3 In the IR spectrum of the prototype, compound 5a exhibited absorption band of carbonyl group at 1722 cm À1 and hydroxyl group at 3439 cm À1 . The 1 H NMR displayed two singlets at d 2.39 and 3.65 for methyl and methylene protons, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…2). [10][11][12] It is well known that certain coumarin derivatives are transformed to other heterocycles such as pyrazoles [13] and pyrimidines [14] by their reaction with hydrazine hydrate and acetamidine or benzimidine, involving the cleavage of the lactone, respectively. The reaction of 4-formyl coumarins with phenyl hydrazine resulted in pyridazines.…”

Section: Efficient and Convenient Methods For Synthesis Of Benzofuran-mentioning

confidence: 99%

Efficient and Convenient Method for Synthesis of Benzofuran-3-acetic Acids and Naphthafuran-acetic Acids

Basanagouda¹,

Narayanachar

Majati³

et al. 2015

Synthetic Communications

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Herein, we report an efficient and convenient method for synthesis of benzofuran-3-acetic acids and naphthafuran-acetic acids 5a-p by the reaction of substituted-4-bromomethylcoumarins with aqueous sodium hydroxide at refluxing temperature. The obtained products are characterized by infrared, 1 H NMR, 13 C NMR, and mass spectral data. Structures 5a and 5e are confirmed by their single x-ray diffraction studies. The advantages of this method are good yields, easy workup, and no chromatographic purifications.

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“…FFA1 (GPR40) is highly expressed in the pancreatic β-cells and is activated by saturated and unsaturated LCFAs and to a less extent by MCFAs, resulting in enhancement of glucose-stimulated insulin secretion, and was thus identified as a new potential target for treatment of type 2 diabetes (Itoh et al, 2003). This observation has attracted much attention, and several series of FFA1 ligands have been identified (Briscoe et al, 2006; Garrido et al, 2006; Song et al, 2007; Christiansen et al, 2008, 2010, 2011, 2012; Tan et al, 2008; Tikhonova et al, 2008; Humphries et al, 2009; Negoro et al, 2010, 2012; Sasaki et al, 2011; Houze et al, 2012; Mikami et al, 2012), of which the most advanced compound has demonstrated good efficacy in phase II studies and currently undergoes phase III clinical trials (Burant et al, 2012). GPR84 and GPR120 respond to MCFAs and LCFAs, respectively.…”

Section: Introductionmentioning

confidence: 99%

Short-chain free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targets

2012

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The deorphanization of the free fatty acid (FFA) receptors FFA1 (GPR40), FFA2 (GPR43), FFA3 (GPR41), GPR84, and GPR120 has made clear that the body is capable of recognizing and responding directly to nonesterified fatty acid of virtually any chain length. Colonic fermentation of dietary fiber produces high concentrations of the short-chain fatty acids (SCFAs) acetate, propionate and butyrate, a process which is important to health. The phylogenetically related 7-transmembrane (7TM) receptors free fatty acid receptor 2 (FFA2) and FFA3 are activated by these SCFAs, and several lines of evidence indicate that FFA2 and FFA3 mediate beneficial effects associated with a fiber-rich diet, and that they may be of interest as targets for treatment of inflammatory and metabolic diseases. FFA2 is highly expressed on immune cells, in particular neutrophils, and several studies suggest that the receptor plays a role in diseases involving a dysfunctional neutrophil response, such as inflammatory bowel disease (IBD). Both FFA2 and FFA3 have been implicated in metabolic diseases such as type 2 diabetes and in regulation of appetite. More research is however required to clarify the potential of the receptors as drug targets and establish if activation or inhibition would be the preferred mode of action. The availability of potent and selective receptor modulators is a prerequisite for these studies. The few modulators of FFA2 or FFA3 that have been published hitherto in the peer-reviewed literature in general have properties that make them less than ideal as such tools, but published patent applications indicate that better tool compounds might soon become available which should enable studies critical to validate the receptors as new drug targets.

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Identification of Fused-Ring Alkanoic Acids with Improved Pharmacokinetic Profiles that Act as G Protein-Coupled Receptor 40/Free Fatty Acid Receptor 1 Agonists

Cited by 62 publications

References 39 publications

Activation of GPR40 as a Therapeutic Target for the Treatment of Type 2 Diabetes

Activation of GPR40 as a Therapeutic Target for the Treatment of Type 2 Diabetes

Efficient and Convenient Method for Synthesis of Benzofuran-3-acetic Acids and Naphthafuran-acetic Acids

Short-chain free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targets

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