31376-92-8Relevant academic research and scientific papers
Design, synthesis, and biological studies of novel 3-benzamidobenzoic acid derivatives as farnesoid X receptor partial agonist
Hu, Lijun,Ren, Qiang,Deng, Liming,Zhou, Zongtao,Cai, Zongyu,Wang, Bin,Li, Zheng
supporting information, (2020/12/25)
Farnesoid X receptor (FXR), a bile acid-activated nuclear receptor, regulates the metabolism of bile acid and lipids as well as maintains the stability of internal environment. FXR was considered as a therapeutic target of liver disorders, such as drug-induced liver injury, fatty liver and cholestasis. The previous reported FXR partial agonist 6 was a suitable lead compound in terms of its high potent and low molecular size, while the docking study of compound 6 suggested a large unoccupied hydrophobic pocket, which might be provided more possibility of structure-activity relationship (SAR) study. In this study, we have performed comprehensive SAR and molecular modeling studies based on lead compound 6. All of these efforts resulted in the identification of a novel series of FXR partial agonists. In this series, compound 41 revealed the best activity and strong interaction with binding pocket of FXR. Moreover, compound 41 protected mice against acetaminophen-induced hepatotoxicity by the regulation of FXR-related gene expression and improving antioxidant capacity. In summary, these results suggest that compound 41 is a promising FXR partial agonist suitable for further investigation.
Design, synthesis and biological evaluation of novel FFA1/GPR40 agonists: New breakthrough in an old scaffold
Li,Liu, Chunxia,Yang, Jianyong,Zhou,Ye, Zhiwen,Feng,Yue, Na,Tong,Huang, Wenlong,Qian, Hai
supporting information, p. 608 - 622 (2019/07/05)
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.
Discovery of phenylsulfonyl acetic acid derivatives with improved efficacy and safety as potent free fatty acid receptor 1 agonists for the treatment of type 2 diabetes
Li, Zheng,Liu, Chunxia,Xu, Xue,Qiu, Qianqian,Su, Xin,Dai, Yuxuan,Yang, Jianyong,Li, Huilan,Shi, Wei,Liao, Chen,Pan, Miaobo,Huang, Wenlong,Qian, Hai
, p. 458 - 479 (2017/07/10)
The free fatty acid receptor 1 (FFA1) has emerged as an attractive anti-diabetic target that mediates glucose-stimulated insulin secretion. Several FFA1 agonists have been reported, but many of them possessed somewhat high lipophilicity and/or molecular weight. Herein, we describe the identification of sulfone-carboxylic acid moiety with the multiple advantages of reducing lipophilicity, cytotoxicity and β-oxidation associated with compound 2. Further structure-activity relationship study based on the previleged scaffolds led to the discovery of 2-{(4-[(2’-chloro-[1,1’-biphenyl]-3-yl)methoxy]phenyl)sulfonyl}acetic acid (compound 20), which showed a better balance than compound 2 in terms of physicochemical properties, cytotoxicity profiles and pharmacokinetic properties. Subsequent in vivo studies demonstrated that compound 20 robustly improves the glucose tolerance both in normal and type 2 diabetic models without the risk of hypoglycemia. Compared to the high risk of TAK-875 induced liver toxicity, there was no significant adverse effects such as hepatic and renal toxicity were observed in the chronic toxicity studies of compound 20 even at the higher dose.
Discovery of a novel oxime ether scaffold as potent and orally bioavailable free fatty acid receptor 1 agonists
Li, Zheng,Yang, Jianyong,Gu, Weijie,Cao, Guoshen,Fu, Xiaoting,Sun, Xuedan,Zhang, Yu,Jin, Hui,Huang, Wenlong,Qian, Hai
, p. 46356 - 46365 (2016/06/09)
The free fatty acid receptor 1 (FFA1) plays a key role in amplifying glucose-stimulated insulin secretion in pancreatic β-cells. Most of the reported FFA1 agonists contain a biphenyl scaffold, which is associated with toxicity as verified by Daiichi Sankyo. Herein, we describe the systematic exploration of a non-biphenyl scaffold to improve the druggability of GW9508 (β-oxidation, Fsp3 = 0.13, tPSA = 58.5 ?2) directed by Fsp3 and tPSA values. All these optimizations ultimately led to the identification of compound 21, an unconventional agonist (EC50 = 72.5 nM) bearing a methyl oxime ether scaffold. Moreover, compound 21 revealed improved drug-like properties (Fsp3 = 0.23, tPSA = 86.6 ?2) when compared to GW9508 (Fsp3 = 0.13, tPSA = 58.5 ?2) and an even higher binding efficiency index (BEI = 15.3) than TAK-875 (BEI = 14.3). Further pharmacological studies suggested that compound 21 has a considerable hypoglycemic effect in both normal and type 2 diabetic mice with a low risk of hypoglycemia. In addition, the docking study promoted our understanding of the ligand-binding pocket. This information might help towards the design of more promising new molecular entities.
Novel oxime ether derivative and preparation method thereof and application of derivative by serving as drug
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Paragraph 0103; 0105; 0106, (2016/10/08)
The invention relates to a novel oxime ether derivative shown as a general formula (I) (please see the formula in the description) and a preparation method thereof and application of a pharmaceutical composition containing the derivative in preparation of a drug for treating diabetes and a metabolic syndrome. The oxime ether derivative has the excellent in-vivo hypoglycemic activity and can be used for preventing or treating the diabetes.
Method for synthesizing oxime ether compound based on C-N bond breakage
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Paragraph 0093; 0094; 0095, (2017/01/26)
The invention relates to a method for synthesizing an oxime ether compound based on C-N bond breakage. The method comprises the step of making a compound shown in equation (1) and a compound show in equation (2) react in the presence of peroxide and an organic solvent to obtain the oxime ether compound as shown in formula (3), and reaction expression is shown in the description. According to the method, synthesis path is short, starting materials are simple, reaction condition is mild, the peroxide is cheap and free of pollution, substrate range is wide, products are easy to separate, and adaptability is high when reaction is amplified to be at the gram grade.
SUBSTITUTED HETEROCYCLIC DERIVATIVES AS GPR AGONISTS AND USES THEREOF
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Page/Page column 107, (2015/03/16)
The present invention generally relates to substituted heterocyclic derivatives (the compounds of Formula (I)), processes for their preparation, pharmaceutical compositions containing said compounds, their use as G-protein coupled receptor (GPR) agonists, particularly as GPR40 agonists and methods of using these compounds in the treatment of GPR40 mediated diseases or conditions such as Type 2 diabetes, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.
PROCESS FOR THE PREPARATION OF AN ARYL OXIME AND SALTS THEREOF
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Page/Page column 47, (2013/05/09)
The invention relates to a process for the preparation of 3-cyano-3-{4-[(4-{[(2Z)-2-(methoxyimino)-2-phenylethyl] oxy} benzyl) oxy] phenyl} propanoic acid or salts thereof. In one form, the invention relates to the process for the preparation of (-)-3-cyano-3-{4-[(4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}benzyl)oxy]phenyl}propanoic acid and conversion of the (-)-enantiomer to the sodium salt, sodium 3-cyano-3-{4-[(4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}benzyl)oxy] phenyl}propanoate.
The first catalytic inverse-electron demand hetero-Diels-Alder reaction of nitroso alkenes using pyrrolidine as an organocatalyst
Wabnitz, Tobias C.,Saaby, Steen,Jorgensen, Karl Anker
, p. 828 - 834 (2007/10/03)
The first catalytic inverse-electron demand hetero-Diels-Alder reaction of nitroso alkenes has been developed. Nitroso alkenes were generated in situ from α-halooximes and underwent [4 + 2]-cycloadditions with enamines as dienophiles formed from aldehydes and pyrrolidine (10 mol%) as an organocatalyst, The presence of a suitable heterogeneous buffer system was found to be essential and best results were obtained with sodium acetate trihydrate. The resulting 5,6-dihydro-4H-oxazines were obtained in moderate to good yields under mild reaction conditions. A catalytic cycle has been proposed and evidence for the cycloaddition mechanism has been obtained. Moderate asymmetric induction (42% ee) was observed when a chiral secondary amine was used.
ORGANIC PHOSPHORUS COMPOUNDS 105 SYNTHESIS AND PROPERTIES OF 2-AMINO-2-ARYLETHYLPHOSPHONIC ACIDS AND DERIVATIVES
Maier, Ludwig,Diel, Peter J.
, p. 245 - 256 (2007/10/03)
2-Amino-2-arylethylphosphonic acids, 6a to 6q have been prepared from the corresponding 2-acetoxyimino- or 2-methoxyimino-2-aryl-ethylphosphonates, 3 or 4, by hydrogenation using Raney-Ni as a catalyst, followed by hydrolysis with HCl. 3 and 4 were obtain
