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
An asymmetric synthesis of 2-arylpiperazines starting from phenacyl bromides, a variety of which are easily available, has been established. The synthesis features a CBS reduction of phenacyl bromide to provide optically enriched compounds, an SN2 reaction of 1,2,3-oxathiazolidine 2-oxides with an azide anion with invert of configuration, and construction of the piperazine ring via reduction of piperazine-2,3-diones.
Subject(s)
Piperazines/chemistry , Acetophenones/chemistry , Diketopiperazines/chemistry , Isomerism , Oxidation-Reduction , Piperazines/chemical synthesisABSTRACT
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
Extensive SAR studies on the unselective BRS3 agonist, [H-D-Phe6,beta-Ala11,Phe13,Nle14]-bombesin-(6-14)-nonapeptide amide, have highlighted structural features important for BRS3 activity and have provided guidance as to the design of selective agonists. A radically modified heptapeptide agonist, maintaining only the Trp-Ala moiety of the parent [H-D-Phe6,betaAla11,Phe13,Nle14]-peptide amide, and with a very different carboxyl terminal region, has been produced which was potent at BRS3 and essentially had no NMB or GRP receptor activity. Its structure is Ac-Phe-Trp-Ala-His(tauBzl)-Nip-Gly-Arg-NH2.
Subject(s)
Bombesin/analogs & derivatives , Drug Design , Receptors, Bombesin/agonists , Receptors, Bombesin/metabolism , Amino Acid Sequence , Animals , Bombesin/chemical synthesis , Bombesin/chemistry , Cell Line , Humans , Ligands , Mice , Models, Molecular , Molecular Sequence Data , Protein Conformation , Substrate SpecificityABSTRACT
Mice lacking a functional bombesin receptor subtype-3 (BRS-3) develop mild obesity. However, the origin of obesity in BRS-3 knockout (KO) mice remains unclear. We used a strain-crossing strategy to investigate the physiological role of the BRS-3 pathway. We crossed female heterozygous BRS-3 KO mice (X-/X) and male KK-Ay mice (Ay/+) to obtain BRS-3 KO/KK-Ay hybrid animals. In X-/Y:Ay/+ mice, plasma insulin concentrations were significantly higher, and on the oral glucose tolerance test, the additional secretion of insulin was impaired compared to other genotypes. Our results indicate that the BRS-3 pathway contributes to the regulation of plasma insulin concentrations.
