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.
MeSH terms
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Animals
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Biological Availability
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Carbamates / chemical synthesis
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Carbamates / chemistry
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Carbamates / pharmacology
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Crystallography, X-Ray
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Dogs
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High-Throughput Screening Assays
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Humans
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Models, Molecular
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Molecular Structure
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Oxadiazoles / chemical synthesis*
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Oxadiazoles / chemistry
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Oxadiazoles / pharmacology
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Piperidines / chemical synthesis
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Piperidines / chemistry
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Piperidines / pharmacology
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacology
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Rats
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Rats, Wistar
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Receptors, G-Protein-Coupled / agonists*
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Receptors, G-Protein-Coupled / chemistry
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Receptors, G-Protein-Coupled / metabolism
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Small Molecule Libraries
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Solubility
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Stereoisomerism
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Structure-Activity Relationship
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Sulfones / chemical synthesis
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Sulfones / chemistry
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Sulfones / pharmacology
Substances
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4-(((2-(2-methyl-4-(5-(1-methylethyl)-1,2,4-oxadiazol-3-yl)piperazin-1-yl)pyrimidin-5-yl)oxy)methyl)pyridine-3-carbonitrile
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Carbamates
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GPR119 protein, human
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Gpr119 protein, mouse
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Oxadiazoles
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Piperidines
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Pyridines
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Receptors, G-Protein-Coupled
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Small Molecule Libraries
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Sulfones