ABSTRACT
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
Although daily low-intensity pulsed ultrasound (LIPUS) can accelerate osteogenic differentiation of the rat clonal cell line ROS 17/2.8, the molecular mechanism that underlies this phenomenon is unclear. The purpose of this study was to determine which molecules exposed to daily LIPUS treatment stimulate osteogenic differentiation. The cells were cultured in the presence and absence (control) of LIPUS stimulation. LIPUS treatments consisted of 1.5-MHz ultrasound administered at an intensity of 30 mW/cm(2), 20 min daily for 7 days. The expression of bone morphogenetic proteins (BMPs) and their receptors involved in osteogenesis were measured using real-time PCR and/or Western blot analysis. Phosphorylation of the mothers against decapentaplegic 1 (Smad1) protein was determined by Western blotting. Daily LIPUS treatment significantly increased the expression of BMP-2, -4, and -7 and their receptors, and also phosphorylation of Smad1. Noggin markedly inhibited the daily LIPUS-induced phosphorylation of Smad1. Our findings demonstrate that the osteogenic activity of daily LIPUS may be mediated by BMPs in ROS 17/2.8 cells.
Subject(s)
Bone Morphogenetic Proteins/analysis , Osteoblasts/metabolism , Ultrasonics , Animals , Blotting, Western , Bone Morphogenetic Protein 2/analysis , Bone Morphogenetic Protein 4/analysis , Bone Morphogenetic Protein 7/analysis , Bone Morphogenetic Protein Receptors/analysis , Bone Morphogenetic Proteins/antagonists & inhibitors , Carrier Proteins/pharmacology , Cell Differentiation , Cell Line , Clone Cells , Cystine Knot Motifs , Electrophoresis, Polyacrylamide Gel , Phosphorylation , Rats , Reverse Transcriptase Polymerase Chain Reaction , Smad1 Protein/analysisABSTRACT
BACKGROUND: An experimental study of rabbit calvaria evaluated the suitability of porous beta-tricalcium phosphate (beta-TCP) block as a biomaterial for onlay bone grafting and determined whether the addition of platelet-rich plasma (PRP) can accelerate bone formation inside the pores of the beta-TCP block. METHODS: In eight rabbits, the calvarium was exposed, and the marrow was penetrated. The beta-TCP blocks were made of Ca3(CO4)3 (porosity, 75%; diameter, 8 mm; thickness, 5 mm). For the experimental group, the blocks were treated with PRP; for the control group, the blocks were treated with venous blood only. Each block was placed in the bone, attached with a titanium screw, and covered with a cutaneous flap. The animals were sacrificed after 3 months, and the tissue ingrowth into the blocks was euthanized. RESULTS: Histologic and histomorphometric measurements demonstrated that there was no inflammatory infiltration around the blocks in either group. New bone formation inside the blocks originated from the parent bone in both groups. The mineralized bone generated tended to climb along the inner walls of the block. In addition, mineralized bone formation was noted around the titanium screw. Furthermore, there was no significant difference between the experimental and control groups in the relative amounts of newly generated tissue and mineralized bone generated in the blocks. CONCLUSION: Porous beta-TCP block is a promising biomaterial for clinical situations requiring bone augmentation; however, the addition of PRP did not induce significantly more new bone formation.
Subject(s)
Bone Substitutes , Calcium Phosphates , Osteogenesis , Platelet-Rich Plasma/physiology , Animals , Male , Porosity , Rabbits , Skull/surgery , Statistics, NonparametricABSTRACT
Two new flavonolignans, mururins A and B ( 1 and 2), and a new lignan, mururin C ( 3), were isolated from the bark of Brosimum acutifolium Huber together with three known lignans. Their structures were elucidated by spectroscopic means and chemical modifications. They were tested for protein kinase A (PKA) and protein kinase C (PKC) inhibitory activity. Mururin A showed 3 % and 63 % inhibition to PKA and PKC, respectively, at 20 microM. Mururin B showed 58 % and 38 % inhibition, respectively. Mururin C did not have significant activity.
