Synthesis and biological evaluation of phenoxyacetic acid derivatives as novel free fatty acid receptor 1 agonists

Wang, Xuekun; Zhao, Tianxiao; Yang, Baowei; Li, Zheng; Cui, Jian; Dai, Yuxuan; Qiu, Qianqian; Hao, Qiang; Huang, Wenlong; Qian, Hai

doi:10.1016/j.bmc.2014.11.016

Cited by 31 publications

(19 citation statements)

References 26 publications

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“…Compound 64 exhibited a significantly improved glucose tolerance, both in normal and diabetic mice, without hypoglycemic side effect. In addition, compound 64 revealed an acceptable PK profile (CL = 0.11 L/hr/kg, t 1/2, iv = 4.15 hr, AUC po, 0–8 hr = 5.34 μg·hr/mL, F = 63%) in rats …”

Section: Synthetic Ffar1 Agonists Based On Different Strategiesmentioning

confidence: 96%

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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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Section: Synthetic Ffar1 Agonists Based On Different Strategiesmentioning

confidence: 96%

“…In addition, compound 64 revealed an acceptable PK profile (CL = 0.11 L/hr/kg, t 1/2, iv = 4.15 hr, AUC po, 0-8 hr = 5.34 μg·hr/mL, F = 63%) in rats. 150,151…”

Section: University Of Southern Denmarkmentioning

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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“…A useful approach to avoiding β‐oxidation is to perform bioisosteric replacements at β carbon using a heteroatom. Wang and colleagues explored the use of a phenoxyacetic acid subunit to the genesis of new agonists of GPR40 . Starting from derivative 6 and using the classical bioisosteric replacement associated with keeping mesylpropoxy group at the biphenyl subunit, such as for TAK‐875 ( 2 ), his research group was able to identify compound 11 , with EC 50 = 62.3 n m , which has potency comparable to TAK‐875 (EC 50 = 38.6 n m ).…”

Section: Gpr40 Agonistsmentioning

confidence: 99%

“…Docking studies showed that the molecular recognition of 11 and TAK‐875 ( 2 ) by GPR40 involved similar intermolecular interactions. However, derivative 11 presented a higher lipophilicity profile, cLog P = 4.05, which was used as a starting point for the optimization of this drug‐like property . Furthermore, due to interruption of the β‐oxidation, the compound had high oral bioavailability, that is, 63% (Figure ) …”

Section: Gpr40 Agonistsmentioning

confidence: 99%

Structural basis for the agonist action at free fatty acid receptor 1 (FFA1R or GPR40)

et al. 2017

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G-protein-coupled receptor 40 (GPR40) was recently identified as an interesting target for treatment of type 2 diabetes. The high level of expression in pancreatic beta cells and the dependence of glucose on stimulating the secretion of insulin led to great excitement in this field. The identification of this target was followed by the development of a series of agonists with great potential for the treatment of diabetes. All known agonists have the presence of a pharmacophoric carboxylic acid group in their structure, which makes several polar interactions at the binding site of this receptor. In this report, we provide a review of the structure-activity relationships of GPR40 agonists with a focus on the main strategies of medicinal chemistry used to develop each one of the main structural patterns exploited for this purpose. Additionally, we provide a general model for the design of GPR40 ligands that can help researchers to follow up some strategies and implement them in the development of novel agonists of this receptor.

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“…1), [9][10][11][12][13][14][15][16][17] and the compounds TAK-875, AMG-837 and LY2881835 were in clinical trials for treatment of T2DM. However, many of these agonists have relatively high molecular weight and lipophilicity (red mark in Fig.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and structure–activity relationship studies of novel phenoxyacetamide-based free fatty acid receptor 1 agonists for the treatment of type 2 diabetes

Wang

Xue

et al. 2015

Bioorganic & Medicinal Chemistry

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Synthesis and biological evaluation of phenoxyacetic acid derivatives as novel free fatty acid receptor 1 agonists

Cited by 31 publications

References 26 publications

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

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

Structural basis for the agonist action at free fatty acid receptor 1 (FFA1R or GPR40)

Design, synthesis and structure–activity relationship studies of novel phenoxyacetamide-based free fatty acid receptor 1 agonists for the treatment of type 2 diabetes

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