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 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Journal of Medicinal Chemistry
Vol/bind	56
Udgave nummer	3
Sider (fra-til)	982-992
Antal sider	11
ISSN	0022-2623
DOI	https://doi.org/10.1021/jm301470a
Status	Udgivet - 14 feb. 2013
Udgivet eksternt	Ja

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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, bind 56, nr. 3, s. 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.",

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",

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

year = "2013",

month = feb,

day = "14",

doi = "10.1021/jm301470a",

language = "English",

volume = "56",

pages = "982--992",

journal = "Journal of Medicinal Chemistry",

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TY - JOUR

T1 - Discovery of a potent and selective free fatty acid receptor 1 agonist with low lipophilicity and high oral bioavailability

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

Y1 - 2013/2/14

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

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