Discovery of novel selective GPR120 agonists with potent anti-diabetic activity by hybrid design

Ren Sheng; Liu Yang; Yanchun Zhang; Enming Xing; Rui Shi; Xiaoan Wen; Heyao Wang; Hongbin Sun

doi:10.1016/j.bmcl.2018.06.047

Discovery of novel selective GPR120 agonists with potent anti-diabetic activity by hybrid design

Bioorg Med Chem Lett. 2018 Aug 15;28(15):2599-2604. doi: 10.1016/j.bmcl.2018.06.047. Epub 2018 Jun 28.

Authors

Ren Sheng¹, Liu Yang², Yanchun Zhang¹, Enming Xing¹, Rui Shi¹, Xiaoan Wen¹, Heyao Wang³, Hongbin Sun⁴

Affiliations

¹ Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China.
² State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
³ State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
⁴ Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China. Electronic address: hongbinsun@cpu.edu.cn.

PMID: 29980358
DOI: 10.1016/j.bmcl.2018.06.047

Abstract

GPR120 is an attractive target for the treatment of type 2 diabetes. In this study, a series of biphenyl derivatives were designed, synthesized by hybrid design. The selected compound 6a exhibited potent GPR120 agonist activity (EC₅₀ = 93 nM) and high selectivity over GPR40. The results of oral glucose tolerance test (OGTT) demonstrated that 6a exhibited significant glucose-lowering effect in glucose-loaded ICR male mice. Analysis of the structure-activity relationship is also presented. Compound 6a deserves further biological evaluation and structural modifications.

Keywords: Agonist biphenyl derivatives; GPR120; OGTT; Type 2 diabetes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biphenyl Compounds / administration & dosage
Biphenyl Compounds / chemistry
Biphenyl Compounds / pharmacology*
Biphenyl Compounds / therapeutic use
Blood Glucose / analysis
Diabetes Mellitus, Experimental / blood
Diabetes Mellitus, Experimental / drug therapy
Diabetes Mellitus, Type 2 / blood
Diabetes Mellitus, Type 2 / drug therapy
Dose-Response Relationship, Drug
Drug Discovery*
Glucose Tolerance Test
Hypoglycemic Agents / administration & dosage
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / pharmacology*
Hypoglycemic Agents / therapeutic use
Male
Mice, Inbred ICR
Receptors, G-Protein-Coupled / agonists*
Structure-Activity Relationship

Substances

Biphenyl Compounds
Blood Glucose
FFAR4 protein, mouse
Hypoglycemic Agents
Receptors, G-Protein-Coupled