Structure-Activity Study of Dihydrocinnamic Acids and Discovery of the Potent FFA1 (GPR40) Agonist TUG-469

  • ACS Med Chem Lett. 2010 Jul 2;1(7):345-9. doi: 10.1021/ml100106c.
Elisabeth Christiansen  1 ,  Maria E Due-Hansen  1 ,  Christian Urban  2 ,  Nicole Merten  3 ,  Michael Pfleiderer  4 ,  Kasper K Karlsen  1 ,  Sanne S Rasmussen  1 ,  Mette Steensgaard  1 ,  Alexandra Hamacher  2 ,  Johannes Schmidt  3 ,  Christel Drewke  3 ,  Rasmus Koefoed Petersen  5 ,  Karsten Kristiansen  5 ,  Susanne Ullrich  4 ,  Evi Kostenis  3 ,  Matthias U Kassack  2 ,  Trond Ulven  1
Affiliations
  • 1. Department of Physics and Chemistry, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
  • 2. Pharmaceutical Biochemistry, Institute of Pharmaceutical and Medicinal Chemistry, University of Düsseldorf, Universitätsstrasse 1, D-40225 Düsseldorf, Germany.
  • 3. Department of Molecular, Cellular and Pharmacobiology Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, D-53115 Bonn, Germany.
  • 4. Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University of Tübingen, Otfried-Müller-Strasse 10, D-72076 Tübingen, Germany.
  • 5. Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark.
PMID: 24900217 DOI: 10.1021/ml100106c
Abstract

The free fatty acid 1 receptor (FFA1 or GPR40), which is highly expressed on pancreatic β-cells and amplifies glucose-stimulated Insulin secretion, has emerged as an attractive target for the treatment of type 2 diabetes. Several FFA1 agonists containing the para-substituted dihydrocinnamic acid moiety are known. We here present a structure-activity relationship study of this compound family suggesting that the central methyleneoxy linker is preferable for the smaller compounds, whereas the central methyleneamine linker gives higher potency to the larger compounds. The study resulted in the discovery of the potent and selective full FFA1 agonist TUG-469 (29).

Keywords
Diabetes; FFA1; FFAR1; GPR40; drug discovery; fatty acids.
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