ABSTRACT
Excessive activation of poly (ADP-ribose) polymerase-1 (PARP-1) is known to develop neuronal apoptosis, necrosis and inflammation after ischaemic brain injury. Therefore, PARP-1 inhibition after ischaemic stroke has been attempted in successful animal studies. The purpose of present work was to develop a novel water soluble PARP-1 inhibitor (JPI-289) and explore its neuroprotective effect on ischaemic injury in an in vitro model. The half-life of JPI-289 after intravenous or oral administration in rats was relatively long (1.4-1.5 hours) with 65.6% bioavailability. The inhibitor strongly inhibited PARP-1 activity (IC50 =18.5 nmol/L) and cellular PAR formation (IC50 =10.7 nmol/L) in the nanomolar range. In rat cortical neuronal cells, JPI-289 did not affect cell viability up to 1 mmol/L as assayed by Trypan blue staining (TBS) and lactate dehydrogenase (LDH) assay. Treatment of JPI-289 for 2 hours after 2 hours of oxygen glucose deprived (OGD) rat cortical neuron attenuated PARP activity and restored ATP and NAD+ levels. Apoptosis-associated molecules such as apoptosis inducing factor (AIF), cytochrome C and cleaved caspase-3 were reduced after JPI-289 treatment in the OGD model. The present findings suggest that the novel PARP-1 inhibitor, JPI-289, is a potential neuroprotective agent which could be useful as a treatment for acute ischaemic stroke.
Subject(s)
Brain/cytology , Enzyme Inhibitors/pharmacology , Naphthyridines/pharmacology , Neurons/drug effects , Neuroprotective Agents/pharmacology , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , Animals , Apoptosis/drug effects , Brain/drug effects , Cell Hypoxia/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Intracellular Space/drug effects , Intracellular Space/metabolism , Naphthyridines/chemistry , Naphthyridines/pharmacokinetics , Neurons/cytology , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacokinetics , Rats , Signal Transduction/drug effects , SolubilityABSTRACT
Inactivation of the NF-κB signaling pathway by inhibition of IKKß is a well-known approach to treat inflammatory diseases such as rheumatoid arthritis and cancer. Thienopyrimidine-based analogues were designed through modification of the known IKKß inhibitor, SPC-839, and then biologically evaluated. The resulting analogues had good inhibitory activity against both nitric oxide and TNF-α, which are well-known inflammatory responses generated by activated NF-κB. However, no inhibitory activity against IKKß was observed with these compounds. The thienopyrimidine-based analogues were subsequently screened for a target kinase, and FLT3, which is a potential target for acute myeloid leukemia (AML), was identified. Thienopyrimidine-based FLT3 inhibitors showed good inhibition profiles against FLT3 under 1µM. Overall, these compounds represent a promising family of inhibitors for future development of a treatment for AML.
Subject(s)
I-kappa B Kinase/antagonists & inhibitors , Pyrimidines/chemical synthesis , Small Molecule Libraries/chemistry , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Enzyme Activation/drug effects , Humans , I-kappa B Kinase/chemistry , Maleimides/chemistry , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Quinazolines/chemistry , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/pharmacologyABSTRACT
A series of coumarin based TACE inhibitors were designed to bind in S1' pocket of TACE enzyme based on their docking study. Twelve analogues were synthesized and most of compounds were active in vitro TACE enzyme inhibition as well as cellular TNF-α inhibition. Among these, 15l effectively inhibited the production of serum TNF-α by oral administration at a dose of 30 mg/kg. Compound 15l also showed a good oral bioavailability at 42% and effectively inhibited paw edema in rat carrageenan model. Quantitative structure-activity relationship (QSAR) study using genetic function approximation technique (GFA) and docking study were performed to confirm the series of coumarin core TACE inhibitors. QSAR model have been evaluated internally and externally using test set prediction. Through docking study of each molecule, it is validated that the electrostatic descriptors from the QSAR equation could explain the importance of S1' pocket and the TACE inhibitory activity well.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Coumarins , Quantitative Structure-Activity Relationship , ADAM17 Protein , Animals , Benzopyrans , Binding Sites , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Protein Binding , Rats , Static ElectricityABSTRACT
Highly potent poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors, including 9-hydroxy-1,2-dihydro-4H-thiopyrano[3,4-c]quinolin-5(6H)-one derivatives with a non-aromatic A-ring, were synthesized. Among the derivatives, 12a showed low nanomolar enzyme and cellular activity (IC(50) = 42 nM, ED(50) = 220 nM) with good water solubility. Further, 12a exhibited microsomal stability in vitro and brain permeability in vivo.
Subject(s)
Amides/pharmacology , Enzyme Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors , Poly(ADP-ribose) Polymerases/metabolism , Polycyclic Compounds/pharmacology , Amides/chemistry , Amides/pharmacokinetics , Animals , Brain/metabolism , CHO Cells , Cricetinae , Cricetulus , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Humans , Microsomes, Liver/metabolism , Models, Molecular , Poly (ADP-Ribose) Polymerase-1 , Poly(ADP-ribose) Polymerases/chemistry , Polycyclic Compounds/chemistry , Polycyclic Compounds/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
A series of coumarin types MMP inhibitors were designed based on gelastatin hydroxamates (1) and evaluated for TACE, cellular TNF-alpha, and NO inhibitory activities. Among them, compounds 9b had potent inhibitory activities in enzymatic and cellular assays and good selectivity to MMP-2 and MMP-9. Further investigation of 9b will be carried out for its efficacy in RA animal model system.
Subject(s)
Coumarins , Metalloendopeptidases/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , ADAM Proteins/antagonists & inhibitors , ADAM17 Protein , Hydroxamic Acids , Matrix Metalloproteinase Inhibitors , Nitric Oxide/antagonists & inhibitors , Protease Inhibitors/pharmacology , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
Anti-glycation activity of our anti-oxidant quinone library was measured and several 2,3-dimethoxy-5-methyl-1,4-benzoquinones and 2-methyl-1,4-naphthoquinones were identified as novel inhibitors of glycation, of which 2,3-dimethoxy-5-methyl-1,4-benzoquinones 13b is the most potent glycation inhibitor with around 50 microM of the IC(50) value.
Subject(s)
Benzoquinones/chemical synthesis , Glycosylation/drug effects , Lipid Peroxidation/drug effects , Naphthoquinones/chemical synthesis , Animals , Antioxidants/chemical synthesis , Antioxidants/pharmacology , Benzoquinones/pharmacology , Glycation End Products, Advanced/antagonists & inhibitors , Humans , Inhibitory Concentration 50 , Naphthoquinones/pharmacology , Structure-Activity RelationshipABSTRACT
4-Hydroxyphenylacetic acid amides and 4-hydroxycinnamamides were synthesized and their antioxidant and neuroprotective activities were evaluated. Among the prepared compounds, 8b, and exhibited potent inhibition of lipid peroxidation in rat brain homogenates, and marked DPPH radical scavenging activities. Furthermore, and exhibited neuroprotective action against the oxidative damage induced by the exposure of primary cultured rat cortical cells to H(2)O(2), xanthine/xanthine oxidase, or Fe(2+)/ascorbic acid. Based on these results, we found that was the most potent antioxidant among the compounds tested.
