1000414-38-9Relevant articles and documents
Identification of highly potent and orally available free fatty acid receptor 1 agonists bearing isoxazole scaffold
Li, Zheng,Liu, Chunxia,Shi, Wei,Cai, Xingguang,Dai, Yuxuan,Liao, Chen,Huang, Wenlong,Qian, Hai
, p. 703 - 711 (2018)
The free fatty acid receptor 1 (FFA1) is being considered to be a novel anti-diabetic target based on its role in amplifying insulin secretion. We have previously identified several series of FFA1 agonists with different heterocyclic scaffolds. Herein, we describe the structural exploration of other heterocyclic scaffolds directed by drug-like physicochemical properties. Further structure-based design and chiral resolution provided the most potent compound 11 (EC50 = 7.9 nM), which exhibited improved lipophilicity (LogD7.4: 1.93), ligand efficiency (LE = 0.32) and ligand lipophilicity efficiency (LLE = 6.2). Moreover, compound 11 revealed an even better pharmacokinetic property than that of TAK-875 in terms of plasma clearance, maximum concentration, and plasma exposure. Although robust agonistic activity and PK profiles for compound 11, the glucose-lowering effects in vivo is not ideal, and the exact reason for in vitro/in vivo difference was worthy for further exploration.
Iridium-Catalyzed Enantioselective Hydrogenation of Indole and Benzofuran Derivatives
Ge, Yao,Wang, Zheng,Han, Zhaobin,Ding, Kuiling
, p. 15482 - 15486 (2020)
Enantioselective hydrogenation of a broad spectrum of N-, O-, and S-containing aromatic benzoheterocycles or nonaromatic unsaturated heterocycles has been realized by using an Ir/SpinPHOX (SpinPHOX=spiro[4,4]-1,6-nonadiene-based phosphine-oxazoline) complex as the catalyst, affording an array of the corresponding chiral benzoheterocycles (30 examples) with excellent enantioselectivities (>99 % ee in most cases) and turnover numbers up to 500.
GPR40 receptor stimulant, and preparation method, pharmaceutical composition and application thereof
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, (2019/10/15)
The invention discloses a GPR40 receptor stimulant, and a preparation method, a pharmaceutical composition and application thereof. The invention particularly discloses a GPR40 receptor stimulant shown in general formula (I) and pharmacologically acceptable salt thereof, a preparation process of the compound, a pharmaceutical composition containing the compound of general formula (I), and application of the compound and the pharmaceutical composition in anti-diabetes.
Design, synthesis and biological evaluation of a series of novel GPR40 agonists containing nitrogen heterocyclic rings
Sun, Zhaozhu,Zhou, Tian,Pan, Xuan,Yang, Ying,Huan, Yi,Xiao, Zhiyan,Shen, Zhufang,Liu, Zhanzhu
, p. 3050 - 3056 (2018/08/11)
A novel series of GPR40 agonists is designed by introducing nitrogen-containing heterocyclic ring at the terminal phenyl ring of TAK-875 with the aim of decreasing its lipophilicity. Three different β-substituted phenylpropionic acids were investigated as the acidic components. A total of 34 compounds have been synthesized, among which, compound 30 exhibited comparable GPR40 agonistic activity in vitro with TAK-875 and relatively lower lipophilicity through calculation (30, EC50 = 1.2 μM, cLogP = 1.3; TAK-875: EC50 = 5.1 μM, cLogP = 3.4). Moreover, compound 30 was able to enhance the insulin secretion of primary islets isolated from normal ICR mice and showed no obvious inhibition against cytochromes P450 in vitro. In vivo, compound 30 exhibited efficacy in oral glucose tolerance test (oGTT) in normal ICR mice.