Identification of a potent and selective free fatty acid receptor 1 (FFA1/GPR40) agonist with favorable physicochemical and in vitro ADME properties

Elisabeth Christiansen; Christian Urban; Manuel Grundmann; Maria Elisabeth Due-Hansen; Ellen Hagesaether; Johannes Schmidt; Leonardo Pardo; Susanne Ullrich; Evi Kostenis; Matthias U Kassack; Trond Ulven

doi:10.1021/jm2005699

Identification of a potent and selective free fatty acid receptor 1 (FFA1/GPR40) agonist with favorable physicochemical and in vitro ADME properties

Elisabeth Christiansen, Christian Urban, Manuel Grundmann, Maria Elisabeth Due-Hansen, Ellen Hagesaether, Johannes Schmidt, Leonardo Pardo, Susanne Ullrich, Evi Kostenis, Matthias U Kassack, Trond Ulven

58 Citations (Scopus)

Abstract

The free fatty acid receptor 1 (FFA1, also known as GPR40) enhances glucose-stimulated insulin secretion from pancreatic β-cells and is recognized as an interesting new target for treatment of type 2 diabetes. Several series of selective FFA1 agonists are already known. Most of these are derived from free fatty acids (FFAs) or glitazones and are relatively lipophilic. Aiming for the development of potent, selective, and less lipophilic FFA1 agonists, the terminal phenyl of a known compound series was replaced by nitrogen containing heterocycles. This resulted in the identification of 37, a selective FFA1 agonist with potent activity on recombinant human FFA1 receptors and on the rat insulinoma cell line INS-1E, optimal lipophilicity, and excellent in vitro permeability and metabolic stability.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	54
Issue number	19
Pages (from-to)	6691-6703
Number of pages	13
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm2005699
Publication status	Published - 13 Oct 2011
Externally published	Yes

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Christiansen, E., Urban, C., Grundmann, M., Due-Hansen, M. E., Hagesaether, E., Schmidt, J., Pardo, L., Ullrich, S., Kostenis, E., Kassack, M. U., & Ulven, T. (2011). Identification of a potent and selective free fatty acid receptor 1 (FFA1/GPR40) agonist with favorable physicochemical and in vitro ADME properties. Journal of Medicinal Chemistry, 54(19), 6691-6703. https://doi.org/10.1021/jm2005699

Identification of a potent and selective free fatty acid receptor 1 (FFA1/GPR40) agonist with favorable physicochemical and in vitro ADME properties. / Christiansen, Elisabeth; Urban, Christian; Grundmann, Manuel et al.

In: Journal of Medicinal Chemistry, Vol. 54, No. 19, 13.10.2011, p. 6691-6703.

Research output: Contribution to journal › Journal article › Research › peer-review

Christiansen, E, Urban, C, Grundmann, M, Due-Hansen, ME, Hagesaether, E, Schmidt, J, Pardo, L, Ullrich, S, Kostenis, E, Kassack, MU & Ulven, T 2011, 'Identification of a potent and selective free fatty acid receptor 1 (FFA1/GPR40) agonist with favorable physicochemical and in vitro ADME properties', Journal of Medicinal Chemistry, vol. 54, no. 19, pp. 6691-6703. https://doi.org/10.1021/jm2005699

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abstract = "The free fatty acid receptor 1 (FFA1, also known as GPR40) enhances glucose-stimulated insulin secretion from pancreatic β-cells and is recognized as an interesting new target for treatment of type 2 diabetes. Several series of selective FFA1 agonists are already known. Most of these are derived from free fatty acids (FFAs) or glitazones and are relatively lipophilic. Aiming for the development of potent, selective, and less lipophilic FFA1 agonists, the terminal phenyl of a known compound series was replaced by nitrogen containing heterocycles. This resulted in the identification of 37, a selective FFA1 agonist with potent activity on recombinant human FFA1 receptors and on the rat insulinoma cell line INS-1E, optimal lipophilicity, and excellent in vitro permeability and metabolic stability.",

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T1 - Identification of a potent and selective free fatty acid receptor 1 (FFA1/GPR40) agonist with favorable physicochemical and in vitro ADME properties

AU - Christiansen, Elisabeth

AU - Urban, Christian

AU - Grundmann, Manuel

AU - Due-Hansen, Maria Elisabeth

AU - Hagesaether, Ellen

AU - Schmidt, Johannes

AU - Pardo, Leonardo

AU - Ullrich, Susanne

AU - Kostenis, Evi

AU - Kassack, Matthias U

AU - Ulven, Trond

PY - 2011/10/13

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N2 - The free fatty acid receptor 1 (FFA1, also known as GPR40) enhances glucose-stimulated insulin secretion from pancreatic β-cells and is recognized as an interesting new target for treatment of type 2 diabetes. Several series of selective FFA1 agonists are already known. Most of these are derived from free fatty acids (FFAs) or glitazones and are relatively lipophilic. Aiming for the development of potent, selective, and less lipophilic FFA1 agonists, the terminal phenyl of a known compound series was replaced by nitrogen containing heterocycles. This resulted in the identification of 37, a selective FFA1 agonist with potent activity on recombinant human FFA1 receptors and on the rat insulinoma cell line INS-1E, optimal lipophilicity, and excellent in vitro permeability and metabolic stability.

AB - The free fatty acid receptor 1 (FFA1, also known as GPR40) enhances glucose-stimulated insulin secretion from pancreatic β-cells and is recognized as an interesting new target for treatment of type 2 diabetes. Several series of selective FFA1 agonists are already known. Most of these are derived from free fatty acids (FFAs) or glitazones and are relatively lipophilic. Aiming for the development of potent, selective, and less lipophilic FFA1 agonists, the terminal phenyl of a known compound series was replaced by nitrogen containing heterocycles. This resulted in the identification of 37, a selective FFA1 agonist with potent activity on recombinant human FFA1 receptors and on the rat insulinoma cell line INS-1E, optimal lipophilicity, and excellent in vitro permeability and metabolic stability.

U2 - 10.1021/jm2005699

DO - 10.1021/jm2005699

M3 - Journal article

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JF - Journal of Medicinal Chemistry

IS - 19

ER -

Identification of a potent and selective free fatty acid receptor 1 (FFA1/GPR40) agonist with favorable physicochemical and in vitro ADME properties

Abstract

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