Discovery of novel free fatty acid receptor 1 agonists bearing triazole core via click chemistry

Zheng Li; Jianyong Yang; Xuekun Wang; Huilan Li; Chunxia Liu; Nasi Wang; Wenlong Huang; Hai Qian

doi:10.1016/j.bmc.2016.08.068

Discovery of novel free fatty acid receptor 1 agonists bearing triazole core via click chemistry

Bioorg Med Chem. 2016 Nov 1;24(21):5449-5454. doi: 10.1016/j.bmc.2016.08.068. Epub 2016 Sep 1.

Authors

Zheng Li¹, Jianyong Yang¹, Xuekun Wang¹, Huilan Li¹, Chunxia Liu¹, Nasi Wang¹, Wenlong Huang², Hai Qian³

Affiliations

¹ Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
² Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: [email protected].
³ Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: [email protected].

PMID: 27624524
DOI: 10.1016/j.bmc.2016.08.068

Abstract

The free fatty acid receptor 1 (FFA1/GPR40) is a novel antidiabetic target based on particular mechanism in enhancing glucose-stimulated insulin secretion. Most of reported FFA1 agonists, however, have been suffered from relatively high lipophilicity and molecular weight. Aiming to develop potent agonists with improved physicochemical property, 25 compounds containing triazole scaffold and various carboxylic acid fragments were synthesized via the click chemistry. Among them, the optimal lead compound 26 with relatively low lipophicity (LogD_7.4=1.95) and molecular weight (Mw = 391.78) exhibited a considerable FFA1 agonistic activity (36.15%). In addition, compound 26 revealed a significant improvement in the glucose tolerance with a 21.4% and 14.2% reduction of glucose AUC_0-2h in normal ICR mice and type 2 diabetic C57BL/6 mice, respectively. All of these results demonstrated that compound 26 was considered to be a promising lead compound suitable for further optimization.

Keywords: Click chemistry; FFA1 agonist; GPR40; Triazole core; Type 2 diabetes.

Publication types

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

MeSH terms

Animals
Blood Glucose / drug effects
Click Chemistry
Diabetes Mellitus, Type 2 / drug therapy*
Dose-Response Relationship, Drug
Drug Discovery*
Glucose Tolerance Test
Humans
Hypoglycemic Agents / chemical synthesis
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / pharmacology*
Male
Mice
Mice, Inbred C57BL
Mice, Inbred ICR
Models, Molecular
Molecular Structure
Receptors, G-Protein-Coupled / agonists*
Structure-Activity Relationship
Triazoles / chemical synthesis
Triazoles / chemistry
Triazoles / pharmacology*

Substances

Blood Glucose
FFAR1 protein, human
Hypoglycemic Agents
Receptors, G-Protein-Coupled
Triazoles