Use of Small-Molecule Crystal Structures To Address Solubility in a Novel Series of G Protein Coupled Receptor 119 Agonists: Optimization of a Lead and in Vivo Evaluation

James S. Scott; Alan M. Birch; Katy J. Brocklehurst; Anders Broo; Hayley S. Brown; Roger J. Butlin; David S. Clarke; Ojvind Davidsson; Anne Ertan; Kristin Goldberg; Sam D. Groombridge; Julian A. Hudson; David Laber; Andrew G. Leach; Philip A. MacFaul; Darren McKerrecher; Adrian Pickup; Paul Schofield; Per H. Svensson; Pernilla Soerme; Joanne Teague

doi:10.1021/jm300310c

Use of Small-Molecule Crystal Structures To Address Solubility in a Novel Series of G Protein Coupled Receptor 119 Agonists: Optimization of a Lead and in Vivo Evaluation

James S. Scott, Alan M. Birch, Katy J. Brocklehurst, Anders Broo, Hayley S. Brown, Roger J. Butlin, David S. Clarke, Ojvind Davidsson, Anne Ertan, Kristin Goldberg, Sam D. Groombridge, Julian A. Hudson, David Laber, Andrew G. Leach, Philip A. MacFaul, Darren McKerrecher, Adrian Pickup, Paul Schofield, Per H. Svensson, Pernilla SoermeJoanne Teague

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

Abstract

G protein coupled receptor 119 (GPR119) is viewed as an attractive target for the treatment of type 2 diabetes and other elements of the metabolic syndrome. During a program toward discovering agonists of GPR119, we herein describe optimization of an initial lead compound, 2, into a development candidate, 42. A key challenge in this program of work was the insolubility of the lead compound. Small-molecule crystallography was utilized to understand the intermolecular interactions in the solid state and resulted in a switch from an aryl sulphone to a 3-cyanopyridyl motif. The compound was shown to be effective in wild-type but not knockout animals, confirming that the biological effects were due to GPR119 agonism.

Original language	English
Pages (from-to)	5361-5379
Number of pages	19
Journal	Journal of Medicinal Chemistry
Volume	55
Issue number	11
DOIs	https://doi.org/10.1021/jm300310c
Publication status	Published - 14 Jun 2012

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Scott, J. S., Birch, A. M., Brocklehurst, K. J., Broo, A., Brown, H. S., Butlin, R. J., Clarke, D. S., Davidsson, O., Ertan, A., Goldberg, K., Groombridge, S. D., Hudson, J. A., Laber, D., Leach, A. G., MacFaul, P. A., McKerrecher, D., Pickup, A., Schofield, P., Svensson, P. H., ... Teague, J. (2012). Use of Small-Molecule Crystal Structures To Address Solubility in a Novel Series of G Protein Coupled Receptor 119 Agonists: Optimization of a Lead and in Vivo Evaluation. Journal of Medicinal Chemistry, 55(11), 5361-5379. https://doi.org/10.1021/jm300310c

@article{c3a2737f116f4e0ab547dce79b481554,

title = "Use of Small-Molecule Crystal Structures To Address Solubility in a Novel Series of G Protein Coupled Receptor 119 Agonists: Optimization of a Lead and in Vivo Evaluation",

abstract = "G protein coupled receptor 119 (GPR119) is viewed as an attractive target for the treatment of type 2 diabetes and other elements of the metabolic syndrome. During a program toward discovering agonists of GPR119, we herein describe optimization of an initial lead compound, 2, into a development candidate, 42. A key challenge in this program of work was the insolubility of the lead compound. Small-molecule crystallography was utilized to understand the intermolecular interactions in the solid state and resulted in a switch from an aryl sulphone to a 3-cyanopyridyl motif. The compound was shown to be effective in wild-type but not knockout animals, confirming that the biological effects were due to GPR119 agonism.",

author = "Scott, {James S.} and Birch, {Alan M.} and Brocklehurst, {Katy J.} and Anders Broo and Brown, {Hayley S.} and Butlin, {Roger J.} and Clarke, {David S.} and Ojvind Davidsson and Anne Ertan and Kristin Goldberg and Groombridge, {Sam D.} and Hudson, {Julian A.} and David Laber and Leach, {Andrew G.} and MacFaul, {Philip A.} and Darren McKerrecher and Adrian Pickup and Paul Schofield and Svensson, {Per H.} and Pernilla Soerme and Joanne Teague",

year = "2012",

month = jun,

day = "14",

doi = "10.1021/jm300310c",

language = "English",

volume = "55",

pages = "5361--5379",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "11",

}

Scott, JS, Birch, AM, Brocklehurst, KJ, Broo, A, Brown, HS, Butlin, RJ, Clarke, DS, Davidsson, O, Ertan, A, Goldberg, K, Groombridge, SD, Hudson, JA, Laber, D, Leach, AG, MacFaul, PA, McKerrecher, D, Pickup, A, Schofield, P, Svensson, PH, Soerme, P & Teague, J 2012, 'Use of Small-Molecule Crystal Structures To Address Solubility in a Novel Series of G Protein Coupled Receptor 119 Agonists: Optimization of a Lead and in Vivo Evaluation', Journal of Medicinal Chemistry, vol. 55, no. 11, pp. 5361-5379. https://doi.org/10.1021/jm300310c

Use of Small-Molecule Crystal Structures To Address Solubility in a Novel Series of G Protein Coupled Receptor 119 Agonists: Optimization of a Lead and in Vivo Evaluation. / Scott, James S.; Birch, Alan M.; Brocklehurst, Katy J. et al.
In: Journal of Medicinal Chemistry, Vol. 55, No. 11, 14.06.2012, p. 5361-5379.

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

TY - JOUR

T1 - Use of Small-Molecule Crystal Structures To Address Solubility in a Novel Series of G Protein Coupled Receptor 119 Agonists

T2 - Optimization of a Lead and in Vivo Evaluation

AU - Scott, James S.

AU - Birch, Alan M.

AU - Brocklehurst, Katy J.

AU - Broo, Anders

AU - Brown, Hayley S.

AU - Butlin, Roger J.

AU - Clarke, David S.

AU - Davidsson, Ojvind

AU - Ertan, Anne

AU - Goldberg, Kristin

AU - Groombridge, Sam D.

AU - Hudson, Julian A.

AU - Laber, David

AU - Leach, Andrew G.

AU - MacFaul, Philip A.

AU - McKerrecher, Darren

AU - Pickup, Adrian

AU - Schofield, Paul

AU - Svensson, Per H.

AU - Soerme, Pernilla

AU - Teague, Joanne

PY - 2012/6/14

Y1 - 2012/6/14

N2 - G protein coupled receptor 119 (GPR119) is viewed as an attractive target for the treatment of type 2 diabetes and other elements of the metabolic syndrome. During a program toward discovering agonists of GPR119, we herein describe optimization of an initial lead compound, 2, into a development candidate, 42. A key challenge in this program of work was the insolubility of the lead compound. Small-molecule crystallography was utilized to understand the intermolecular interactions in the solid state and resulted in a switch from an aryl sulphone to a 3-cyanopyridyl motif. The compound was shown to be effective in wild-type but not knockout animals, confirming that the biological effects were due to GPR119 agonism.

AB - G protein coupled receptor 119 (GPR119) is viewed as an attractive target for the treatment of type 2 diabetes and other elements of the metabolic syndrome. During a program toward discovering agonists of GPR119, we herein describe optimization of an initial lead compound, 2, into a development candidate, 42. A key challenge in this program of work was the insolubility of the lead compound. Small-molecule crystallography was utilized to understand the intermolecular interactions in the solid state and resulted in a switch from an aryl sulphone to a 3-cyanopyridyl motif. The compound was shown to be effective in wild-type but not knockout animals, confirming that the biological effects were due to GPR119 agonism.

U2 - 10.1021/jm300310c

DO - 10.1021/jm300310c

M3 - Article

SN - 0022-2623

VL - 55

SP - 5361

EP - 5379

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 11

ER -

Use of Small-Molecule Crystal Structures To Address Solubility in a Novel Series of G Protein Coupled Receptor 119 Agonists: Optimization of a Lead and in Vivo Evaluation

Abstract

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