Exploring bulky natural and natural-like periphery in the design of p-(benzyloxy)phenylpropionic acid agonists of free fatty acid receptor 1 (GPR40)

[Display omitted] •FFA1 is a clinically validated antidiabetic target with no approved drugs on the market.•3-Phenyl propionic acid is a known mimetic of endogenous ligands of FFA1.•Natural and natural-like amines have been employed as periphery motifs.•Bornyl- and cytisine-bearing compounds were mo...

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Bibliographic Details
Published in:Bioorganic chemistry 2020-06, Vol.99, p.103830, Article 103830
Main Authors: Kuranov, Sergey O., Luzina, Olga A., Onopchenko, Oleksandra, Pishel, Iryna, Zozulya, Sergey, Gureev, Maxim, Salakhutdinov, Nariman F., Krasavin, Mikhail
Format: Article
Language:English
Subjects:
Animals
Biological Products - chemical synthesis
Biological Products - chemistry
Biological Products - pharmacology
Blood Glucose - analysis
Dose-Response Relationship, Drug
Drug Design
Free fatty acid receptor 1
Glucose tolerance
Glucose Tolerance Test
Humans
Male
Mice
Mice, Inbred C57BL
Molecular Structure
Natural products
Natural-likeness
Phenylpropionates - chemical synthesis
Phenylpropionates - chemistry
Phenylpropionates - pharmacology
Receptors, G-Protein-Coupled - agonists
Receptors, G-Protein-Coupled - metabolism
Structure-Activity Relationship
Three-dimensional structure
Type 2 diabetes mellitus
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Summary:[Display omitted] •FFA1 is a clinically validated antidiabetic target with no approved drugs on the market.•3-Phenyl propionic acid is a known mimetic of endogenous ligands of FFA1.•Natural and natural-like amines have been employed as periphery motifs.•Bornyl- and cytisine-bearing compounds were most active in vitro as FFA1 agonists.•In vivo efficacy testing (oGTT) showed the bornyl compound to be the lead compound. 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.
ISSN:0045-2068
1090-2120
DOI:10.1016/j.bioorg.2020.103830