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

被引：59

作者：

Scott, James S. ^{[1
]}

Birch, Alan M. ^{[1
]}

Brocklehurst, Katy J. ^{[1
]}

Broo, Anders ^{[2
]}

Brown, Hayley S. ^{[1
]}

Butlin, Roger J. ^{[1
]}

Clarke, David S. ^{[1
]}

Davidsson, Ojvind ^{[2
]}

Ertan, Anne ^{[3
]}

Goldberg, Kristin ^{[1
]}

Groombridge, Sam D. ^{[1
]}

Hudson, Julian A. ^{[1
]}

Laber, David ^{[1
]}

Leach, Andrew G. ^{[1
]}

MacFaul, Philip A. ^{[1
]}

McKerrecher, Darren ^{[1
]}

Pickup, Adrian ^{[1
]}

Schofield, Paul ^{[1
]}

Svensson, Per H. ^{[3
]}

Soerme, Pernilla ^{[1
]}

Teague, Joanne ^{[1
]}

机构：

[1] AstraZeneca, Cardiovasc & Gastrointestinal Innovat Med Unit, Macclesfield SK10 4TG, Cheshire, England

[2] AstraZeneca, Cardiovasc & Gastrointestinal Innovat Med Unit, S-43183 Molndal, Sweden

[3] AstraZeneca R&D, Pharmaceut Dev, S-15185 Sodertalje, Sweden

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 11期

关键词：

GPR119; AGONIST; AQUEOUS SOLUBILITY; INSULIN-SECRETION; GLYCEMIC CONTROL; DISCOVERY; POTENT; BIOISOSTERES; DISRUPTION; INHIBITORS; AS1535907;

D O I：

10.1021/jm300310c

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：5361 / 5379

页数：19

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