Discovery, optimisation and in vivo evaluation of novel GPR119 agonists

Katy J. Brocklehurst; Anders Broo; Roger J. Butlin; Hayley S. Brown; David S. Clarke; Öjvind Davidsson; Kristin Goldberg; Sam D. Groombridge; Elizabeth E. Kelly; Andrew Leach; Darren McKerrecher; Charles O'Donnell; Simon Poucher; Paul Schofield; James S. Scott; Joanne Teague; Leanne Westgate; Matt J.M. Wood

doi:10.1016/j.bmcl.2011.10.033

Discovery, optimisation and in vivo evaluation of novel GPR119 agonists

Katy J. Brocklehurst, Anders Broo, Roger J. Butlin, Hayley S. Brown, David S. Clarke, Öjvind Davidsson, Kristin Goldberg, Sam D. Groombridge, Elizabeth E. Kelly, Andrew Leach, Darren McKerrecher, Charles O'Donnell, Simon Poucher, Paul Schofield, James S. Scott^*, Joanne Teague, Leanne Westgate, Matt J.M. Wood

^*Corresponding author for this work

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

Abstract

GPR119 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. During a programme aimed at developing agonists of the GPR119 receptor, we identified compounds that were potent with reduced hERG liabilities, that had good pharmacokinetic properties and that displayed excellent glucose-lowering effects in vivo. However, further profiling in a GPR119 knock-out (KO) mouse model revealed that the biological effects were not exclusively due to GPR119 agonism, highlighting the value of transgenic animals in drug discovery programs.

Original language	English
Pages (from-to)	7310-7316
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	24
DOIs	https://doi.org/10.1016/j.bmcl.2011.10.033
Publication status	Published - 15 Dec 2011

Keywords

GPR119 agonist
hERG
Knock-out mice
Transgenic animals

UN SDGs

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

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10.1016/j.bmcl.2011.10.033

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Brocklehurst, K. J., Broo, A., Butlin, R. J., Brown, H. S., Clarke, D. S., Davidsson, Ö., Goldberg, K., Groombridge, S. D., Kelly, E. E., Leach, A., McKerrecher, D., O'Donnell, C., Poucher, S., Schofield, P., Scott, J. S., Teague, J., Westgate, L., & Wood, M. J. M. (2011). Discovery, optimisation and in vivo evaluation of novel GPR119 agonists. Bioorganic and Medicinal Chemistry Letters, 21(24), 7310-7316. https://doi.org/10.1016/j.bmcl.2011.10.033

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title = "Discovery, optimisation and in vivo evaluation of novel GPR119 agonists",

abstract = "GPR119 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. During a programme aimed at developing agonists of the GPR119 receptor, we identified compounds that were potent with reduced hERG liabilities, that had good pharmacokinetic properties and that displayed excellent glucose-lowering effects in vivo. However, further profiling in a GPR119 knock-out (KO) mouse model revealed that the biological effects were not exclusively due to GPR119 agonism, highlighting the value of transgenic animals in drug discovery programs.",

keywords = "GPR119 agonist, hERG, Knock-out mice, Transgenic animals",

author = "Brocklehurst, {Katy J.} and Anders Broo and Butlin, {Roger J.} and Brown, {Hayley S.} and Clarke, {David S.} and {\"O}jvind Davidsson and Kristin Goldberg and Groombridge, {Sam D.} and Kelly, {Elizabeth E.} and Andrew Leach and Darren McKerrecher and Charles O'Donnell and Simon Poucher and Paul Schofield and Scott, {James S.} and Joanne Teague and Leanne Westgate and Wood, {Matt J.M.}",

year = "2011",

month = dec,

day = "15",

doi = "10.1016/j.bmcl.2011.10.033",

language = "English",

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journal = "Bioorganic and Medicinal Chemistry Letters",

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Brocklehurst, KJ, Broo, A, Butlin, RJ, Brown, HS, Clarke, DS, Davidsson, Ö, Goldberg, K, Groombridge, SD, Kelly, EE, Leach, A, McKerrecher, D, O'Donnell, C, Poucher, S, Schofield, P, Scott, JS, Teague, J, Westgate, L & Wood, MJM 2011, 'Discovery, optimisation and in vivo evaluation of novel GPR119 agonists', Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 24, pp. 7310-7316. https://doi.org/10.1016/j.bmcl.2011.10.033

TY - JOUR

T1 - Discovery, optimisation and in vivo evaluation of novel GPR119 agonists

AU - Brocklehurst, Katy J.

AU - Broo, Anders

AU - Butlin, Roger J.

AU - Brown, Hayley S.

AU - Clarke, David S.

AU - Davidsson, Öjvind

AU - Goldberg, Kristin

AU - Groombridge, Sam D.

AU - Kelly, Elizabeth E.

AU - Leach, Andrew

AU - McKerrecher, Darren

AU - O'Donnell, Charles

AU - Poucher, Simon

AU - Schofield, Paul

AU - Scott, James S.

AU - Teague, Joanne

AU - Westgate, Leanne

AU - Wood, Matt J.M.

PY - 2011/12/15

Y1 - 2011/12/15

N2 - GPR119 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. During a programme aimed at developing agonists of the GPR119 receptor, we identified compounds that were potent with reduced hERG liabilities, that had good pharmacokinetic properties and that displayed excellent glucose-lowering effects in vivo. However, further profiling in a GPR119 knock-out (KO) mouse model revealed that the biological effects were not exclusively due to GPR119 agonism, highlighting the value of transgenic animals in drug discovery programs.

AB - GPR119 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. During a programme aimed at developing agonists of the GPR119 receptor, we identified compounds that were potent with reduced hERG liabilities, that had good pharmacokinetic properties and that displayed excellent glucose-lowering effects in vivo. However, further profiling in a GPR119 knock-out (KO) mouse model revealed that the biological effects were not exclusively due to GPR119 agonism, highlighting the value of transgenic animals in drug discovery programs.

KW - GPR119 agonist

KW - hERG

KW - Knock-out mice

KW - Transgenic animals

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M3 - Article

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AN - SCOPUS:81255209244

SN - 0960-894X

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EP - 7316

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 24

ER -

Discovery, optimisation and in vivo evaluation of novel GPR119 agonists

Abstract

Keywords

UN SDGs

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