Highly lipophilic 3-epi-betulinic acid derivatives as potent and selective TGR5 agonists with improved cellular efficacy  

作　　者：Xiao-yin WANG Shu-yong ZHANG Jing LI Hua-nan LIU Xin XIE Fa-jun NAN 

机构地区：[1]State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, ShanghaiInstitute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

出　　处：《Acta Pharmacologica Sinica》2014年第11期1463-1472,共10页中国药理学报（英文版）

基　　金：Acknowledgements This work was supported by grants from the National Science and Technology Major Projects for Major New Drugs Innovation and Development （No 2012ZX09304011, 2013ZX09507001, and 2012ZX09301001-005）, National Basic Research Program of China （973 Program） （No 2014CB541906） and the National Natural Science Foundation of China （No 30725049 and 81202341）,

摘　　要：Aim： TGR5 is a G protein-coupled receptor that is expressed in intestinal L-cells and stimulates glucagon-like peptide 1（GLP-1） secretion. TGR5 may represent a novel target for the treatment of metabolic disorder. Here, we sought to design and synthesize a series of TGR5 agonists derived from the natural product betuiinic acid. Methods： A series of betulinic acid derivatives were designed and synthesized. A cAMP assay was established using a HEK293 cell line expressing human TGR5. Luciferase reporter assay was established using HEK293 cells transfected with plasmids encoding human FXR and luciferase reporter. A human intestinal L-cell line NCI-H716 was used to evaluate the effects of the betulinic acid derivatives on GLP-1 secretion in vitro. Results; Biological data revealed that the 3-a-OH triterpenoids consistently show increased potency for TGR5 compared to their 3-β- OH epimers. 3-OH esterification increased the lipophilicity and TGR5 activity of 3-cc betulinic derivatives and enhanced the activity differences between 3-α and 3-β derivatives. The 3-α-acyloxy betulinic acids also exhibited a significant dose-dependent GLP-1 secretion effect. Conclusion： This study demonstrates that highly lipophilic 3-epi-betulinic acid derivatives can be potent and selective TGR5 agonists with improved cellular efficacy, and our research here provides a new strategy for the design and development of potent TGR5 agonists.Aim： TGR5 is a G protein-coupled receptor that is expressed in intestinal L-cells and stimulates glucagon-like peptide 1（GLP-1） secretion. TGR5 may represent a novel target for the treatment of metabolic disorder. Here, we sought to design and synthesize a series of TGR5 agonists derived from the natural product betuiinic acid. Methods： A series of betulinic acid derivatives were designed and synthesized. A cAMP assay was established using a HEK293 cell line expressing human TGR5. Luciferase reporter assay was established using HEK293 cells transfected with plasmids encoding human FXR and luciferase reporter. A human intestinal L-cell line NCI-H716 was used to evaluate the effects of the betulinic acid derivatives on GLP-1 secretion in vitro. Results; Biological data revealed that the 3-a-OH triterpenoids consistently show increased potency for TGR5 compared to their 3-β- OH epimers. 3-OH esterification increased the lipophilicity and TGR5 activity of 3-cc betulinic derivatives and enhanced the activity differences between 3-α and 3-β derivatives. The 3-α-acyloxy betulinic acids also exhibited a significant dose-dependent GLP-1 secretion effect. Conclusion： This study demonstrates that highly lipophilic 3-epi-betulinic acid derivatives can be potent and selective TGR5 agonists with improved cellular efficacy, and our research here provides a new strategy for the design and development of potent TGR5 agonists.

关 键 词：TGR5 ACTIVATOR betulinic acid derivatives GLP-1 LIPOPHILIC structure modifications 

分 类 号：Q57[生物学—生物化学] O636.1[理学—高分子化学]