Discovery of a Potent Free Fatty Acid 1 Receptor Agonist with Low Lipophilicity, Low Polar Surface Area, and Robust in Vivo Efficacy

The free fatty acid receptor 1 (FFA1 or GPR40) is established as an interesting potential target for treatment of type 2 diabetes. However, to obtain optimal ligands, it may be necessary to limit both lipophilicity and polar surface area, translating to a need for small compounds. We here describe t...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2016-03, Vol.59 (6), p.2841-2846
Main Authors: Hansen, Steffen V. F, Christiansen, Elisabeth, Urban, Christian, Hudson, Brian D, Stocker, Claire J, Due-Hansen, Maria E, Wargent, Ed T, Shimpukade, Bharat, Almeida, Reinaldo, Ejsing, Christer S, Cawthorne, Michael A, Kassack, Matthias U, Milligan, Graeme, Ulven, Trond
Format: Article
Language:English
Subjects:
Animals
Blood Glucose - metabolism
Diabetes Mellitus, Type 2 - drug therapy
Drug Discovery
Glucose Tolerance Test
Hypoglycemic Agents - chemical synthesis
Hypoglycemic Agents - pharmacology
Ligands
Lipids - chemistry
Mice
Mice, Inbred C57BL
Models, Molecular
Phenylpropionates - chemical synthesis
Phenylpropionates - pharmacology
Receptors, G-Protein-Coupled - agonists
Structure-Activity Relationship
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Summary:The free fatty acid receptor 1 (FFA1 or GPR40) is established as an interesting potential target for treatment of type 2 diabetes. However, to obtain optimal ligands, it may be necessary to limit both lipophilicity and polar surface area, translating to a need for small compounds. We here describe the identification of 24, a potent FFA1 agonist with low lipophilicity and very high ligand efficiency that exhibit robust glucose lowering effect.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.5b01962