- Nitric oxide donor-based FFA1 agonists: Design, synthesis and biological evaluation as potential anti-diabetic and anti-thrombotic agents
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The cardiovascular complications were highly prevalent in type 2 diabetes mellitus (T2DM), even at the early stage of T2DM or the state of intensive glycemic control. Thus, there is an urgent need for the intervention of cardiovascular complications in T2DM. Herein, the new hybrids of FFA1 agonist and NO donor were design to obtain dual effects of anti-hyperglycemic and anti-thrombosis. As expected, the induced-fit docking study suggested that it is feasible for our design strategy to hybrid NO donor with compound 1. These hybrids exhibited moderate FFA1 agonistic activities and anti-platelet aggregation activities, and their anti-platelet effects mediated by NO were also confirmed in the presence of NO scavenger. Moreover, compound 3 revealed significantly hypoglycemic effect and even stronger than that of TAK-875 during an oral glucose tolerance test in mice. Potent and multifunctional hybrid, such as compound 3, is expected as a potential candidate with additional cardiovascular benefits for the treatment of T2DM.
- Li, Zheng,Xu, Xue,Liu, Roujia,Deng, Fengjian,Zeng, Xiaohua,Zhang, Luyong
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Read Online
- SULFINIC ACID COMPOUNDS AS FREE FATTY ACID RECEPTOR AGONISTS
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The present invention relates to certain compounds, their use in therapy, as well as to pharmaceutical compositions including said compounds. Specifically, the invention relates to certain compounds and pharmaceutical compositions including these compounds for the treatment of metabolic disorders including, for example, diabetes, obesity, metabolic syndrome, fatty liver disease, and bone disorders.
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Page/Page column 99
(2021/02/19)
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- Design, synthesis and biological evaluation of novel FFA1/GPR40 agonists: New breakthrough in an old scaffold
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Based on an old phenoxyacetic acid scaffold, CPU014 (compound 14) has been identified as a superior agonist by comprehensive exploration of structure-activity relationship. In vitro toxicity study suggested that CPU014 has lower risk of hepatotoxicity than TAK-875. During acute toxicity study (5–500 mg/kg), a favorable therapeutic window of CPU014 was observed by evaluation of plasma profiles and liver slices. Moreover, CPU014 promotes insulin secretion in a glucose-dependent manner, while no GLP-1 secretion has been enhanced. Other than good pharmacokinetic properties, CPU014 significantly improved glucose tolerance both in normal and diabetic models without the risk of hypoglycemia. These subversive findings provided a safer candidate CPU014, which is currently in preclinical study to assess its potential for the treatment of diabetes.
- Li,Liu, Chunxia,Yang, Jianyong,Zhou,Ye, Zhiwen,Feng,Yue, Na,Tong,Huang, Wenlong,Qian, Hai
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p. 608 - 622
(2019/07/05)
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- Discovery of HWL-088: A highly potent FFA1/GPR40 agonist bearing a phenoxyacetic acid scaffold
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Based on a previously reported phenoxyacetic acid scaffold, compound 7 (HWL-088) has been identified as a superior free fatty acid receptor 1 (FFA1) agonist by comprehensive structure-activity relationship study. Our results indicated that the introduction of ortho-fluoro greatly increased the activity of phenoxyacetic acid series, and the unique structure-activity relationship in biphenyl moiety is different from previously reported FFA1 agonists. Moreover, the modeling study was also performed to better understand the binding mode of present series. Compound 7 significantly improved glucose tolerance both in normal and diabetic models, and even exerted greater potential on glucose control than that of TAK-875. These findings provided a novel candidate HWL-088, which is currently in preclinical study to evaluate its potential for the treatment of diabetes.
- Li, Zheng,Ren, Qiang,Wang, Xuekun,Zhou, Zongtao,Hu, Lijun,Deng, Liming,Guan, Li,Qiu, Qianqian
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- Design, synthesis, and evaluation of a series of novel phenylpropanoic acid derivatives agonists for the FFA1
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Free fatty acid 1 (FFA1/GPR40) has attracted extensive attention as a novel target for the treatment of type 2 diabetes for its role in the enhancement of insulin secretion with glucose dependency. Aiming to develop novel potent FFA1 agonists, a new series of phenylpropionic acid derivatives were designed and synthesized on the basis of the modification of chemical cement of TAK-875, AMG-837, and LY2881835. Among them, most promising compounds 7, 14, and 15 were obtained with EC50 values of 82, 79, and 88?nM, exhibiting a powerful agonistic activity compared to TAK-875 (95.1?nM). During Oral glucose tolerance test in normal mice, compound 7, 14, and 15 had significant glucose-lowering effect at the dose of 50?mg/kg. Furthermore, compound 15 (50?mg/kg) also significantly improved in glucose tolerance in type 2 diabetic mice. Herein, we reported the discovery and optimization of a series of potent FFA1 agonists. The discovery supported further exploration surrounding this scaffold.
- Yang, Jiaju,Gu, Enke,Yan, Ting,Shen, Daoming,Feng, Bainian,Tang, Chunlei
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p. 900 - 909
(2019/02/05)
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- 4-diphenylcarboxylic acid compound and preparing method and application thereof
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The invention relates to a 4-diphenylcarboxylic acid compound and a preparing method and application thereof, and belongs to the field of medicines. The 4-diphenylcarboxylic acid compound is shown inthe formula I. The 4-diphenylcarboxylic acid compound ex
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Paragraph 0117; 0118; 0125; 0126
(2018/06/21)
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- A novel phenoxyacetic acid derivatives, their preparation and their use as medicaments (by machine translation)
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The invention relates to a compound of general formula (I) indicated by the model phenoxyacetic acid derivatives, preparation method thereof and containing the pharmaceutical composition as a preparation for the treatment of diabetes and metabolic syndrome in pharmaceutical use. The phenoxyacetic acid derivatives have an excellent in vivo hypoglycemic activity, it can be used for preventing or treating diabetes. (by machine translation)
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Paragraph 0096-0098
(2017/10/07)
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- (S) - 2 - (2,3-dihydrobenzo-furan-3-yl) acetic acid derivatives, its preparation process and its use in medicine
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The invention relates to an (S)-2-(2,3-dihydrobenzofuran-3-radical) acetic acid derivative, a preparation method of the derivative, a medicine composition containing the derivative and the application of the derivative serving as a therapeutic agent, particularly GPR40/FFA1, and particularly provides the (S)-2-(2,3-dihydrobenzofuran-3-radical) acetic acid derivative shown in a general formula (I), and pharmaceutically acceptable salts of the derivative or a prodrug of the derivative. The compound is an agonist of a GPR40/FFA1 receptor and has a good preventive and therapeutic effect on lots of GPR40-mediated diseases, especially diabetes mellitus. The invention also provides a preparation method of the compound.
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Paragraph 0106-0108
(2016/10/08)
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- TAK-875 analog, and preparation method and application thereof
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The invention relates to a TAK-875 analog, and a preparation method and an application thereof, concretely relates to a compound with a structure represented by general formula (I), and various optical isomers, pharmaceutically acceptable salts, solvates
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Paragraph g0064; 0065
(2016/10/27)
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- CARBOXYLIC ACID COMPOUNDS IN TREATMENT OF DIABETES MELLITUS
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The invention relates to compounds for increasing GPR40 recetpor activity and application thereof. These compounds include of a compound of Formula (I), pharmaceutically acceptable salts thereof, solvates thereof, isomers thereof, or produgs of the compou
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Page/Page column 30; 31
(2015/03/13)
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- Design, synthesis and biological activity of phenoxyacetic acid derivatives as novel free fatty acid receptor 1 agonists
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The free fatty acid receptor 1 (FFA1) is a novel antidiabetic target for the treatment of type 2 diabetes based on particular mechanism in amplifying glucose-stimulated insulin secretion. We have previously identified a series of phenoxyacetic acid deriva
- Li, Zheng,Wang, Xuekun,Xu, Xue,Yang, Jianyong,Xia, Wenting,Zhou, Xianhao,Huang, Wenlong,Qian, Hai
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supporting information
p. 7158 - 7164
(2015/11/16)
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- BIPHENYL COMPOUNDS AND USES THEREOF
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The present invention relates to biphenyl compounds and uses thereof in medicine. Specifically, the present invention relates to a compound of Formula (I), or a stereoisomer, a geometric isomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereoisomer, an N-oxide, a hydrate, a solvate, a metabolite, a hydrolysate, a pharmaceutically acceptable salt or a prodrug thereof. The compound disclosed herein is used as a therapeutic agent particularly a GPR40 agonist for treating diabetes and metabolic disease in a patient.
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Paragraph 00143
(2015/05/19)
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- Discovery of phenylpropanoic acid derivatives containing polar functionalities as potent and orally bioavailable G protein-coupled receptor 40 agonists for the treatment of type 2 diabetes
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As part of a program to identify potent GPR40 agonists with drug-like properties suitable for clinical development, the incorporation of polar substituents was explored with the intention of decreasing the lipophilicity of our recently disclosed phenylpropanoic acid derivative 1. This incorporation would allow us to mitigate the cytotoxicity issues observed with compound 1 and enable us to move away from the multifunctional free fatty acid-like structure. Substitutions on the 2′,6′-dimethylbiphenyl ring were initially undertaken, which revealed the feasibility of introducing polar functionalities at the biphenyl 4′-position. Further optimization of this position and the linker led to the discovery of several 4′-alkoxybiphenyl derivatives, which showed potent GPR40 agonist activities with the best balance in terms of improved cytotoxicity profiles and favorable pharmacokinetic properties. Among them, 3-{2-fluoro-4-[({4′-[(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran- 4-yl)methoxy]-2′,6′-dimethylbiphenyl-3-yl}methyl)amino]phenyl} propanoic acid (35) exhibited a robust plasma glucose-lowering effect and insulinotropic action during an oral glucose tolerance test in rats with impaired glucose tolerance.
- Mikami, Satoshi,Kitamura, Shuji,Negoro, Nobuyuki,Sasaki, Shinobu,Suzuki, Masami,Tsujihata, Yoshiyuki,Miyazaki, Takeshi,Ito, Ryo,Suzuki, Nobuhiro,Miyazaki, Junichi,Santou, Takashi,Kanzaki, Naoyuki,Funami, Miyuki,Tanaka, Toshimasa,Yasuma, Tsuneo,Momose, Yu
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experimental part
p. 3756 - 3776
(2012/07/30)
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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
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The G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. We previously identified phenylpropanoic acid derivative 1 (3-{4-[(2′,6′-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl} propanoic acid) as a potent and orally available GPR40/FFA1 agonist; however, 1 exhibited high clearance and low oral bioavailability, which was likely due to its susceptibility to β-oxidation at the phenylpropanoic acid moiety. To identify long-acting compounds, we attempted to block the metabolically labile sites at the phenylpropanoic acid moiety by introducing a fused-ring structure. Various fused-ring alkanoic acids with potent GPR40/FFA1 activities and good PK profiles were produced. Further optimizations of the lipophilic portion and the acidic moiety led to the discovery of dihydrobenzofuran derivative 53 ((6-{[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methoxy} -2,3-dihydro-1-benzofuran-3-yl)acetic acid), which acted as a GPR40/FFA1 agonist with in vivo efficacy during an oral glucose tolerance test (OGTT) in rats with impaired glucose tolerance.
- 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, Yu
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scheme or table
p. 1538 - 1552
(2012/04/10)
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- FUSED CYCLIC COMPOUNDS
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The present invention provides a compound represented by the formula (I): wherein each symbol is as defined in the description, or a salt thereof. The compound or a salt thereof or a prodrug thereof has a GPR40 receptor function modulating action and is useful as an insulin secretagogue or an agent for the prophylaxis or treatment of diabetes and the like.
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Page/Page column 74
(2008/06/13)
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- CYCLOPROPANECARBOXYLIC ACID COMPOUND
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A compound of the formula (I): wherein each symbol is as defined in the description, a salt thereof, and a prodrug thereof of the present invention unexpectedly have a superior GPR40 receptor agonist activity and superior properties as pharmaceutical prod
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Page/Page column 26-27
(2010/11/30)
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- AMINOPHENYLPROPANOIC ACID DERIVATIVE
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A compound represented by the formula (1): wherein each symbol is as defined in the specification, and a salt thereof and a prodrug thereof unexpectedly have superior GPR40 receptor agonist activity, superior in the properties as a pharmaceutical product such as stability and the like, and can be a safe and useful pharmaceutical agent as a drug for the prophylaxis or treatment of GPR40 receptor related pathology or diseases such as diabetes and the like.
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Page/Page column 41
(2010/11/24)
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- 3-(4-BENZYLOXYPHENYL)PROPANOIC ACID DERIVATIVES
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The present invention provides a novel compound represented by the formula (I) wherein each symbol is as defined in the specification, a salt thereof and a prodrug thereof having a superior GPR40 receptor function modulating action, which can be used as an insulin secretagogue, an agent for the prophylaxis or treatment of diabetes and the like. They unexpectedly show superior GPR40 receptor agonist activity, and also show superior properties as a pharmaceutical product, such as stability and the like. Thus, they can be safe and useful pharmaceutical agents for the prophylaxis or treatment of GPR40 receptor related diseases in mammals.
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Page/Page column 85
(2010/02/12)
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