ABSTRACT
We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3ß inhibitors from our promising compounds containing a 3-methylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3ß inhibitors. SAR studies focused on the nitrogen atom of the piperazine moiety revealed that a phenyl group afforded potent inhibitory activity toward GSK-3ß. Docking studies indicated that the phenyl group on the piperazine nitrogen atom and the methyl group on the piperazine make cation-π and CH-π interactions with GSK-3ß respectively. 4-Methoxyphenyl analogue 29 showed most potent inhibitory activity toward GSK-3ß with good in vitro and in vivo pharmacokinetic profiles, and 29 demonstrated a significant decrease in tau phosphorylation after oral administration in mice.
Subject(s)
Drug Discovery , Protein Kinase Inhibitors/pharmacology , Pyrimidinones/pharmacology , Dose-Response Relationship, Drug , Glycogen Synthase Kinase 3 beta/metabolism , Humans , Molecular Docking Simulation , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrimidinones/chemical synthesis , Pyrimidinones/chemistry , Structure-Activity RelationshipABSTRACT
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
Optimization of a new series of S-adenosyl-L-homocysteine hydrolase (AdoHcyase) inhibitors based on non-adenosine analogs led to very potent compounds 14n, 18a, and 18b with IC50 values of 13 ± 3, 5.0 ± 2.0, and 8.5 ± 3.1 nM, respectively. An X-ray crystal structure of AdoHcyase with NAD(+) and 18a showed a novel open form co-crystal structure. 18a in the co-crystals formed intramolecular eight membered ring hydrogen bond formations. A single crystal X-ray structure of 14n also showed an intramolecular eight-membered ring hydrogen bond interaction.
Subject(s)
Adenosylhomocysteinase/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Adenosine/chemistry , Adenosylhomocysteinase/genetics , Adenosylhomocysteinase/metabolism , Binding Sites , Crystallography, X-Ray , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Humans , Hydrogen Bonding , Isomerism , Molecular Conformation , Molecular Dynamics Simulation , NAD/chemistry , NAD/metabolism , Protein Binding , Protein Structure, Tertiary , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Structure-Activity RelationshipABSTRACT
We herein describe the results of further evolution of GSK-3ß inhibitors for Alzheimer's disease from our promising compounds with in vivo tau phosphorylation inhibitory activity by oral administration. Introduction of a low alkyl group instead of the phenyl group at the 3-position of the morpholine moiety aiming to improve pharmacokinetic profiles resulted in potent low molecular weight GSK-3ß inhibitors with good in vitro pharmacokinetic profiles, which also showed in vivo tau phosphorylation inhibitory activity by oral administration. Effect of the stereochemistry of the alkyl moiety is also discussed using docking models.
Subject(s)
Alzheimer Disease/enzymology , Glycogen Synthase Kinase 3/antagonists & inhibitors , Morpholines/chemistry , Morpholines/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Administration, Oral , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Animals , Drug Discovery , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Humans , Mice , Molecular Docking Simulation , Morpholines/administration & dosage , Morpholines/pharmacokinetics , Phosphorylation/drug effects , Pyrimidines/administration & dosage , Pyrimidines/pharmacokinetics , tau Proteins/metabolismABSTRACT
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.
Subject(s)
Glycogen Synthase Kinase 3/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Pyrimidinones/chemistry , Binding Sites , Enzyme Activation , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Molecular Docking Simulation , Protein Binding/drug effects , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Structure, Tertiary , Pyrimidinones/chemical synthesis , Pyrimidinones/metabolism , Pyrimidinones/pharmacology , Structure-Activity RelationshipABSTRACT
Accurate methods to predict the binding affinities of compounds for target molecules are powerful tools in structure-based drug design (SBDD). A recently developed method called massively parallel computation of absolute binding free energy with a well-equilibrated system (MP-CAFEE) successfully predicted the binding affinities of compounds with relatively similar scaffolds. We investigate the applicability of MP-CAFEE for predicting the affinity of compounds having more diverse scaffolds for the target p38α, a mitogen-activated protein kinase. The calculated and experimental binding affinities correlate well, showing that MP-CAFEE can accurately rank the compounds with diverse scaffolds. We propose a method to determine the optimal number of sampling runs with respect to a predefined level of accuracy, which is established according to the stage in the SBDD process being considered. The optimal number of sampling runs for two key stages-lead identification and lead optimization-is estimated to be five and eight or more, respectively, in our model system using Cochrans sample size formula.
