Exploring bulky natural and natural-like periphery in the design of p-(benzyloxy)phenylpropionic acid agonists of free fatty acid receptor 1 (GPR40).
Animals
Biological Products
/ chemical synthesis
Blood Glucose
/ analysis
Dose-Response Relationship, Drug
Drug Design
Glucose Tolerance Test
Humans
Male
Mice
Mice, Inbred C57BL
Molecular Structure
Phenylpropionates
/ chemical synthesis
Receptors, G-Protein-Coupled
/ agonists
Structure-Activity Relationship
Free fatty acid receptor 1
Glucose tolerance
Natural products
Natural-likeness
Three-dimensional structure
Type 2 diabetes mellitus
Journal
Bioorganic chemistry
ISSN: 1090-2120
Titre abrégé: Bioorg Chem
Pays: United States
ID NLM: 1303703
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
03
03
2020
revised:
31
03
2020
accepted:
05
04
2020
pubmed:
15
4
2020
medline:
3
3
2021
entrez:
15
4
2020
Statut:
ppublish
Résumé
Six derivatives of 3-phenylpropionic acid bearing various natural and natural-like, spatially defined peripheral motifs have been synthesized and evaluated in vitro for free fatty acid receptor 1 (FFA1) activation. Two frontrunner compounds (bearing a bornyl and cytosine groups) were evaluated in an oral glucose tolerance test in mice where both demonstrated the ability to sustain blood glucose levels following a glucose challenge. The bornyl compound displayed a somewhat superior, dose-dependent efficacy and, therefore, can be regarded as a lead compounds for further development as a therapeutic agent for type 2 diabetes mellitus. Its high affinity to FFA1 was rationalized by docking experiments.
Identifiants
pubmed: 32289588
pii: S0045-2068(20)30504-6
doi: 10.1016/j.bioorg.2020.103830
pii:
doi:
Substances chimiques
Biological Products
0
Blood Glucose
0
FFAR1 protein, human
0
Phenylpropionates
0
Receptors, G-Protein-Coupled
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
103830Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.