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
| Autor: | David S. Clarke, Adrian Pickup, Andrew G. Leach, Pernilla Sörme, James S. Scott, Kristin Goldberg, Philip A. MacFaul, Julian A. Hudson, David Laber, Per H. Svensson, Darren Mckerrecher, Anders Broo, Katy J. Brocklehurst, Hayley S. Brown, Sam D. Groombridge, Öjvind Davidsson, Joanne Teague, Anne Ertan, Roger John Butlin, Alan Martin Birch, Paul Schofield |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Pyridines Stereochemistry Biological Availability Crystallography X-Ray Receptors G-Protein-Coupled Small Molecule Libraries Mice Structure-Activity Relationship chemistry.chemical_compound Dogs Piperidines In vivo Drug Discovery Animals Humans Structure–activity relationship Sulfones Rats Wistar Receptor G protein-coupled receptor Mice Knockout Oxadiazoles Molecular Structure Chemistry Aryl Stereoisomerism Combinatorial chemistry Small molecule High-Throughput Screening Assays Rats Mice Inbred C57BL Solubility Molecular Medicine Carbamates Lead compound |
| Zdroj: | Journal of Medicinal Chemistry. 55:5361-5379 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm300310c |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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