ABSTRACT
We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3ß inhibitors from our promising compounds containing a 2-phenylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3ß inhibitors. SAR studies focused on the phenyl moiety revealed that a 4-fluoro-2-methoxy group afforded potent inhibitory activity toward GSK-3ß. Based on docking studies, new hydrogen bonding between the nitrogen atom of the piperazine moiety and the oxygen atom of the main chain of Gln185 has been indicated, which may contribute to increased activity compared with that of the corresponding phenylmorpholine analogues. Effect of the stereochemistry of the phenylpiperazine moiety is also discussed.
Subject(s)
Drug Discovery , Piperazines/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyrimidinones/pharmacology , Dose-Response Relationship, Drug , Glycogen Synthase Kinase 3 beta/metabolism , Humans , Molecular Docking Simulation , Molecular Structure , Piperazines/chemical synthesis , Piperazines/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrimidinones/chemical synthesis , Pyrimidinones/chemistry , Structure-Activity RelationshipABSTRACT
The steroidal glucocorticoid antagonist mifepristone has been reported to improve the symptoms of depression. We report the discovery of 6-(3,5-dimethylisoxazol-4-yl)-2,2,4,4-tetramethyl-2,3,4,7,8,9-hexahydro-1H-cyclopenta[h]quinolin-3-one 3d (QCA-1093) as a novel nonsteroidal glucocorticoid receptor antagonist. The compound displayed potent in vitro activity, high selectivity over other steroid hormone receptors, and significant antidepressant-like activity in vivo.
Subject(s)
Antidepressive Agents/chemistry , Antidepressive Agents/therapeutic use , Depression/drug therapy , Quinolines/chemistry , Quinolines/therapeutic use , Receptors, Glucocorticoid/antagonists & inhibitors , Animals , Antidepressive Agents/chemical synthesis , Antidepressive Agents/pharmacology , Cell Line , Humans , Male , Molecular Docking Simulation , Quinolines/chemical synthesis , Quinolines/pharmacology , Rats , Rats, Wistar , Receptors, Glucocorticoid/metabolism , Structure-Activity RelationshipABSTRACT
A series of 2-(2-phenylmorpholin-4-yl)pyrimidin-4(3H)-ones was synthesized and examined for their inhibitory activity against glycogen synthase kinase-3ß (GSK-3ß). We found 21, 29 and 30 to possess potent in vitro GSK-3ß inhibitory activity with good in vitro PK profiles. 21 demonstrated significant decrease of tau phosphorylation after oral administration in mice and excellent PK profiles.
Subject(s)
Glycogen Synthase Kinase 3/antagonists & inhibitors , Morpholines/chemical synthesis , Morpholines/pharmacology , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Administration, Oral , Animals , Binding Sites , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Enzyme Activation/drug effects , Female , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Half-Life , Humans , Male , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Molecular Docking Simulation , Morpholines/pharmacokinetics , Phosphorylation/drug effects , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Protein Structure, Tertiary , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacokinetics , Rats , Rats, Sprague-Dawley , Stereoisomerism , tau Proteins/metabolismABSTRACT
The discovery of a series of 6-(4-pyridyl)pyrimidin-4(3H)-ones derived from a hit compound with low molecular weight and sufficient chemical space is reported. Transformation of substituents led to subnanomolar potent inhibitors with in vivo tau phoshorylation lowering activity.
