Discovery of a potent and selective free fatty acid receptor 1 agonist with low lipophilicity and high oral bioavailability

Elisabeth Christiansen; Maria E Due-Hansen; Christian Urban; Manuel Grundmann; Johannes Schmidt; Steffen V F Hansen; Brian D Hudson; Mohamed Zaibi; Stine B Markussen; Ellen Hagesaether; Graeme Milligan; Michael A Cawthorne; Evi Kostenis; Matthias U Kassack; Trond Ulven

doi:10.1021/jm301470a

Discovery of a potent and selective free fatty acid receptor 1 agonist with low lipophilicity and high oral bioavailability

Elisabeth Christiansen, Maria E Due-Hansen, Christian Urban, Manuel Grundmann, Johannes Schmidt, Steffen V F Hansen, Brian D Hudson, Mohamed Zaibi, Stine B Markussen, Ellen Hagesaether, Graeme Milligan, Michael A Cawthorne, Evi Kostenis, Matthias U Kassack, Trond Ulven

41 Citations (Scopus)

Abstract

The free fatty acid receptor 1 (FFA1, also known as GPR40) mediates enhancement of glucose-stimulated insulin secretion and is emerging as a new target for the treatment of type 2 diabetes. Several FFA1 agonists are known, but the majority of these suffer from high lipophilicity. We have previously reported the FFA1 agonist 3 (TUG-424). We here describe the continued structure-activity exploration and optimization of this compound series, leading to the discovery of the more potent agonist 40, a compound with low lipophilicity, excellent in vitro metabolic stability and permeability, complete oral bioavailability, and appreciable efficacy on glucose tolerance in mice.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	3
Pages (from-to)	982-992
Number of pages	11
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm301470a
Publication status	Published - 14 Feb 2013
Externally published	Yes

Keywords

Administration, Oral
Animals
Biological Availability
Drug Discovery
Magnetic Resonance Spectroscopy
Mice
Models, Molecular
Receptors, G-Protein-Coupled
Spectrometry, Mass, Electrospray Ionization
Structure-Activity Relationship

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/jm301470a

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Christiansen, E., Due-Hansen, M. E., Urban, C., Grundmann, M., Schmidt, J., Hansen, S. V. F., Hudson, B. D., Zaibi, M., Markussen, S. B., Hagesaether, E., Milligan, G., Cawthorne, M. A., Kostenis, E., Kassack, M. U., & Ulven, T. (2013). Discovery of a potent and selective free fatty acid receptor 1 agonist with low lipophilicity and high oral bioavailability. Journal of Medicinal Chemistry, 56(3), 982-992. https://doi.org/10.1021/jm301470a

Christiansen, E, Due-Hansen, ME, Urban, C, Grundmann, M, Schmidt, J, Hansen, SVF, Hudson, BD, Zaibi, M, Markussen, SB, Hagesaether, E, Milligan, G, Cawthorne, MA, Kostenis, E, Kassack, MU & Ulven, T 2013, 'Discovery of a potent and selective free fatty acid receptor 1 agonist with low lipophilicity and high oral bioavailability', Journal of Medicinal Chemistry, vol. 56, no. 3, pp. 982-992. https://doi.org/10.1021/jm301470a

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title = "Discovery of a potent and selective free fatty acid receptor 1 agonist with low lipophilicity and high oral bioavailability",

abstract = "The free fatty acid receptor 1 (FFA1, also known as GPR40) mediates enhancement of glucose-stimulated insulin secretion and is emerging as a new target for the treatment of type 2 diabetes. Several FFA1 agonists are known, but the majority of these suffer from high lipophilicity. We have previously reported the FFA1 agonist 3 (TUG-424). We here describe the continued structure-activity exploration and optimization of this compound series, leading to the discovery of the more potent agonist 40, a compound with low lipophilicity, excellent in vitro metabolic stability and permeability, complete oral bioavailability, and appreciable efficacy on glucose tolerance in mice.",

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doi = "10.1021/jm301470a",

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AU - Christiansen, Elisabeth

AU - Due-Hansen, Maria E

AU - Urban, Christian

AU - Grundmann, Manuel

AU - Schmidt, Johannes

AU - Hansen, Steffen V F

AU - Hudson, Brian D

AU - Zaibi, Mohamed

AU - Markussen, Stine B

AU - Hagesaether, Ellen

AU - Milligan, Graeme

AU - Cawthorne, Michael A

AU - Kostenis, Evi

AU - Kassack, Matthias U

AU - Ulven, Trond

PY - 2013/2/14

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N2 - The free fatty acid receptor 1 (FFA1, also known as GPR40) mediates enhancement of glucose-stimulated insulin secretion and is emerging as a new target for the treatment of type 2 diabetes. Several FFA1 agonists are known, but the majority of these suffer from high lipophilicity. We have previously reported the FFA1 agonist 3 (TUG-424). We here describe the continued structure-activity exploration and optimization of this compound series, leading to the discovery of the more potent agonist 40, a compound with low lipophilicity, excellent in vitro metabolic stability and permeability, complete oral bioavailability, and appreciable efficacy on glucose tolerance in mice.

AB - The free fatty acid receptor 1 (FFA1, also known as GPR40) mediates enhancement of glucose-stimulated insulin secretion and is emerging as a new target for the treatment of type 2 diabetes. Several FFA1 agonists are known, but the majority of these suffer from high lipophilicity. We have previously reported the FFA1 agonist 3 (TUG-424). We here describe the continued structure-activity exploration and optimization of this compound series, leading to the discovery of the more potent agonist 40, a compound with low lipophilicity, excellent in vitro metabolic stability and permeability, complete oral bioavailability, and appreciable efficacy on glucose tolerance in mice.

KW - Administration, Oral

KW - Animals

KW - Biological Availability

KW - Drug Discovery

KW - Magnetic Resonance Spectroscopy

KW - Mice

KW - Models, Molecular

KW - Receptors, G-Protein-Coupled

KW - Spectrometry, Mass, Electrospray Ionization

KW - Structure-Activity Relationship

U2 - 10.1021/jm301470a

DO - 10.1021/jm301470a

M3 - Journal article

SN - 0022-2623

VL - 56

SP - 982

EP - 992

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 3

ER -

Discovery of a potent and selective free fatty acid receptor 1 agonist with low lipophilicity and high oral bioavailability

Abstract

Keywords

UN SDGs

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