480447-26-5Relevant academic research and scientific papers
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.
Synthesis of difunctionalized dendrimers: An approach to main-chain poly(dendrimers)
Ganesh, Renuka N.,Shraberg, Joshua,Sheridan, Patrick G.,Thayumanavan
, p. 7217 - 7220 (2007/10/03)
Synthesis of benzyl ether dendrimers that are difunctionalized at their peripheries are described. These dendrimers should form the basis for a new class of main-chain dendritic polymers. The steric protection afforded at higher generation during the synt
