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

Steffen V F Hansen; Elisabeth Christiansen; Christian Urban; Brian D Hudson; Claire J Stocker; Maria E Due-Hansen; Ed T Wargent; Bharat Shimpukade; Reinaldo Almeida; Christer S Ejsing; Michael A Cawthorne; Matthias U Kassack; Graeme Milligan; Trond Ulven

doi:10.1021/acs.jmedchem.5b01962

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

J Med Chem. 2016 Mar 24;59(6):2841-6. doi: 10.1021/acs.jmedchem.5b01962. Epub 2016 Mar 15.

Affiliations

¹ Department of Physics, Chemistry and Pharmacy, University of Southern Denmark , Campusvej 55, DK-5230 Odense M, Denmark.
² Institute of Pharmaceutical and Medicinal Chemistry, University of Düsseldorf , Universitätsstrasse 1, D-40225 Düsseldorf, Germany.
³ Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow G12 8QQ, Scotland, U.K.
⁴ Clore Laboratory, University of Buckingham , Hunter Street, Buckingham MK18 1EG, U.K.
⁵ Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark , Campusvej 55, DK-5230 Odense M, Denmark.

PMID: 26928019
DOI: 10.1021/acs.jmedchem.5b01962

Abstract

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.

Publication types

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

MeSH terms

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

Substances

3-(2-fluoro-4-(3-methylpent-3-en-1-yn-1-yl)phenyl)propanoic acid
Blood Glucose
Ffar1 protein, mouse
Hypoglycemic Agents
Ligands
Lipids
Phenylpropionates
Receptors, G-Protein-Coupled