Abstract
The synthesis and properties of the bridged piperidine (oxaazabicyclo) compounds 8, 9, and 11 are described. A conformational analysis of these structures is compared with the representative GPR119 ligand 1. These results and the differences in agonist pharmacology are used to formulate a conformation-based hypothesis to understand activation of the GPR119 receptor. We also show for these structures that the agonist pharmacology in rat masks the important differences in human pharmacology.
MeSH terms
-
Animals
-
Azabicyclo Compounds / chemical synthesis
-
Azabicyclo Compounds / chemistry*
-
Azabicyclo Compounds / pharmacology*
-
Glucose Tolerance Test
-
Humans
-
Molecular Conformation
-
Pyrimidines / chemical synthesis
-
Pyrimidines / chemistry*
-
Pyrimidines / pharmacology*
-
Rats
-
Receptors, G-Protein-Coupled / agonists*
-
Receptors, G-Protein-Coupled / antagonists & inhibitors
-
Species Specificity
-
Stereoisomerism
-
Structure-Activity Relationship
Substances
-
Azabicyclo Compounds
-
GPR119 protein, human
-
GPR119 protein, rat
-
Pyrimidines
-
Receptors, G-Protein-Coupled
-
isopropyl 8-(5-methyl-6-(2-methylpyridin-3-yloxy)pyrimidin-4-yloxy)-6-oxa-3-azabicyclo(3.2.1)octane-3-carboxylate
-
isopropyl 9-((5-methyl-6-((2-methylpyridin-3-yl)oxy)pyrimidin-4-yl)oxy)-3-oxa-7-azabicyclo(3.3.1)nonane-7-carboxylate