Discovery of a Potent Free Fatty Acid 1 Receptor Agonist with Low Lipophilicity, Low Polar Surface Area, and Robust in Vivo Efficacy

Steffen V.F. Hansen; Elisabeth Christiansen; Christian Urban; Brian D. Hudson; Claire J. Stocker; Maria E. Due-Hansen; Ed T. Wargent; Bharat Shimpukade; Reinaldo Almeida; Christer S. Ejsing; Michael A. Cawthorne; Matthias U. Kassack; Graeme Milligan; Trond Ulven

doi:10.1021/acs.jmedchem.5b01962

Discovery of a Potent Free Fatty Acid 1 Receptor Agonist with Low Lipophilicity, Low Polar Surface Area, and Robust in Vivo Efficacy

Steffen V.F. Hansen, Elisabeth Christiansen, Christian Urban, Brian D. Hudson, Claire J. Stocker, Maria E. Due-Hansen, Ed T. Wargent, Bharat Shimpukade, Reinaldo Almeida, Christer S. Ejsing, Michael A. Cawthorne, Matthias U. Kassack, Graeme Milligan, Trond Ulven^*

^*Corresponding author for this work

Aston Medical School

Research output: Contribution to journal › Article › peer-review

Abstract

The free fatty acid receptor 1 (FFA1 or GPR40) is established as an interesting potential target for treatment of type 2 diabetes. However, to obtain optimal ligands, it may be necessary to limit both lipophilicity and polar surface area, translating to a need for small compounds. We here describe the identification of 24, a potent FFA1 agonist with low lipophilicity and very high ligand efficiency that exhibit robust glucose lowering effect.

Original language	English
Pages (from-to)	2841-2846
Number of pages	6
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	6
DOIs	https://doi.org/10.1021/acs.jmedchem.5b01962
Publication status	Published - 24 Mar 2016

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© 2016 American Chemical Society.

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Hansen, S. V. F., Christiansen, E., Urban, C., Hudson, B. D., Stocker, C. J., Due-Hansen, M. E., Wargent, E. T., Shimpukade, B., Almeida, R., Ejsing, C. S., Cawthorne, M. A., Kassack, M. U., Milligan, G., & Ulven, T. (2016). Discovery of a Potent Free Fatty Acid 1 Receptor Agonist with Low Lipophilicity, Low Polar Surface Area, and Robust in Vivo Efficacy. Journal of Medicinal Chemistry, 59(6), 2841-2846. https://doi.org/10.1021/acs.jmedchem.5b01962

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title = "Discovery of a Potent Free Fatty Acid 1 Receptor Agonist with Low Lipophilicity, Low Polar Surface Area, and Robust in Vivo Efficacy",

abstract = "The free fatty acid receptor 1 (FFA1 or GPR40) is established as an interesting potential target for treatment of type 2 diabetes. However, to obtain optimal ligands, it may be necessary to limit both lipophilicity and polar surface area, translating to a need for small compounds. We here describe the identification of 24, a potent FFA1 agonist with low lipophilicity and very high ligand efficiency that exhibit robust glucose lowering effect.",

author = "Hansen, {Steffen V.F.} and Elisabeth Christiansen and Christian Urban and Hudson, {Brian D.} and Stocker, {Claire J.} and Due-Hansen, {Maria E.} and Wargent, {Ed T.} and Bharat Shimpukade and Reinaldo Almeida and Ejsing, {Christer S.} and Cawthorne, {Michael A.} and Kassack, {Matthias U.} and Graeme Milligan and Trond Ulven",

note = "Publisher Copyright: {\textcopyright} 2016 American Chemical Society.",

year = "2016",

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doi = "10.1021/acs.jmedchem.5b01962",

language = "English",

volume = "59",

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Hansen, SVF, Christiansen, E, Urban, C, Hudson, BD, Stocker, CJ, Due-Hansen, ME, Wargent, ET, Shimpukade, B, Almeida, R, Ejsing, CS, Cawthorne, MA, Kassack, MU, Milligan, G & Ulven, T 2016, 'Discovery of a Potent Free Fatty Acid 1 Receptor Agonist with Low Lipophilicity, Low Polar Surface Area, and Robust in Vivo Efficacy', Journal of Medicinal Chemistry, vol. 59, no. 6, pp. 2841-2846. https://doi.org/10.1021/acs.jmedchem.5b01962

TY - JOUR

T1 - Discovery of a Potent Free Fatty Acid 1 Receptor Agonist with Low Lipophilicity, Low Polar Surface Area, and Robust in Vivo Efficacy

AU - Hansen, Steffen V.F.

AU - Christiansen, Elisabeth

AU - Urban, Christian

AU - Hudson, Brian D.

AU - Stocker, Claire J.

AU - Due-Hansen, Maria E.

AU - Wargent, Ed T.

AU - Shimpukade, Bharat

AU - Almeida, Reinaldo

AU - Ejsing, Christer S.

AU - Cawthorne, Michael A.

AU - Kassack, Matthias U.

AU - Milligan, Graeme

AU - Ulven, Trond

PY - 2016/3/24

Y1 - 2016/3/24

N2 - The free fatty acid receptor 1 (FFA1 or GPR40) is established as an interesting potential target for treatment of type 2 diabetes. However, to obtain optimal ligands, it may be necessary to limit both lipophilicity and polar surface area, translating to a need for small compounds. We here describe the identification of 24, a potent FFA1 agonist with low lipophilicity and very high ligand efficiency that exhibit robust glucose lowering effect.

AB - The free fatty acid receptor 1 (FFA1 or GPR40) is established as an interesting potential target for treatment of type 2 diabetes. However, to obtain optimal ligands, it may be necessary to limit both lipophilicity and polar surface area, translating to a need for small compounds. We here describe the identification of 24, a potent FFA1 agonist with low lipophilicity and very high ligand efficiency that exhibit robust glucose lowering effect.

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SN - 0022-2623

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SP - 2841

EP - 2846

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 6

ER -

Discovery of a Potent Free Fatty Acid 1 Receptor Agonist with Low Lipophilicity, Low Polar Surface Area, and Robust in Vivo Efficacy

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