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 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Journal of Medicinal Chemistry
Vol/bind	54
Udgave nummer	19
Sider (fra-til)	6691-6703
Antal sider	13
ISSN	0022-2623
DOI	https://doi.org/10.1021/jm2005699
Status	Udgivet - 13 okt. 2011
Udgivet eksternt	Ja

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10.1021/jm2005699

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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.

I: Journal of Medicinal Chemistry, Bind 54, Nr. 19, 13.10.2011, s. 6691-6703.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › 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, bind 54, nr. 19, s. 6691-6703. https://doi.org/10.1021/jm2005699

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

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.",

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

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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

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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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