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. 2010 Jul 2;1(7):345-9.
doi: 10.1021/ml100106c. eCollection 2010 Oct 14.

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

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

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

Elisabeth Christiansen et al. ACS Med Chem Lett. .

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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Figures

Figure 1
Figure 1
Thiazolidinedione and dihydrocinnamic acid FFA1 agonists.,,,,.
Scheme 1
Scheme 1
Scheme 2
Scheme 2
Figure 2
Figure 2
DMR analysis of FFA1 agonists. (a) hFFA1 transfected 1321N1 cells were challenged with the indicated concentrations of 29 (n > 2), and the wavelength shift (pm) was monitored over time as a measure of receptor activation. (b) Dose−response curves: GW9508 pEC50 = 7.06 ± 0.11 (red line); 1 pEC50 = 6.08 ± 0.15 (black line); 28 pEC50 = 6.58 ± 0.09 (gold line); and 29 pEC50 = 7.46 ± 0.06 (blue line).
Figure 3
Figure 3
Effect of 29 on insulin secretion from the pancreatic rat INS-1E β-cells at basal and stimulatory glucose concentrations. Shown are mean values ± SEMs (n = 3). The asterisk indicates significance to 12 mM glucose (p < 0.001).
See this image and copyright information in PMC

References

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