- Characterization and Optimization of Benzimidazopyrimidine and Pyridoimidazopyridine Derivatives as Tau-SPECT Probes
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The accumulation of hyperphosphorylated tau protein in the brain is regarded as one of the hallmarks of Alzheimer's disease (AD). In vivo imaging of tau aggregates is helpful for diagnosis and monitoring of the progression of AD. In this study, we designed and synthesized novel radioiodinated benzimidazopyrimidine (BIPM) and pyridoimidazopyridine (PIP) derivatives with a monomethylamino, monoethylamino, monopropylamino, or diethylamino group as tau imaging probes for single-photon-emission computed tomography (SPECT). On in vitro autoradiography with AD brain sections, [125I]PIP-NHMe showed the highest selective binding affinity for tau aggregates among the radioiodinated BIPM and PIP derivatives. In a biodistribution study using normal mice, [125I]PIP-NHMe and [125I]PIP-NHEt displayed high initial uptake (6.62 and 6.86% ID/g, respectively, at 2 min postinjection) into and rapid clearance from the brain, with brain2 min/brain30 min ratios of 38.9 and 28.6, respectively. These results suggest that [123I]PIP-NHMe may be a novel SPECT probe that is useful for detecting tau aggregates in the AD brain.
- Watanabe, Hiroyuki,Kishimoto, Takeaki,Kaide, Sho,Tarumizu, Yuta,Tatsumi, Haruka,Iikuni, Shimpei,Ono, Masahiro
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Read Online
- TGF-betaR1 inhibitor and application thereof
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The invention belongs to the field of medical chemistry, and particularly relates to a compound serving as a TGF-betaR1 inhibitor and application of the compound. Specifically, the invention providesa compound shown as a formula I or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, a preparation method of the compounds, a pharmaceutical composition containing the compounds and application of the compounds or the composition to treatment and/or prevention of TGF-betaR1 related diseases, such as cancers, tissue hyperplasia diseases, fibrosis and inflammatory diseases. The compound provided by the invention shows significant inhibitory activity on TGF-betaR1 kinase, and is very expected to become a therapeutic agent for TGF-betaR1 related diseases.
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Paragraph 0783; 0785-0787
(2020/06/09)
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- FNEW ACTIVATORS OF SIRT1 ENZYME FOR THE TREATMENT OF CARDIOVASCULAR AND CARDIOMETABOLIC PATHOLOGIES
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This invention describes a class of compounds able to activate the human SIRT1 enzyme and regulate many metabolic functions. This invention relates to compounds that can be employed in medical applications, specifically for the treatment or prevention of cardiometabolic diseases, such as diabetes, and of cardiovascular disorders, such as coronaropathy, heart failure and atherosclerosis.
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Page/Page column 13; 19; 37
(2019/09/12)
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- CHEMICAL COMPOUNDS AS INHIBITORS OF KINASE ACTIVITY
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The invention is directed to certain novel compounds. Specifically, the invention is directed to compounds of formula (I): (I) and salts thereof. The compounds of the invention are inhibitors of kinase activity, in particular PI3- kinase activity.
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Page/Page column 105
(2017/09/05)
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- Pyridylphosphinate metal complexes: Synthesis, structural characterisation and biological activity
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For the first time, a series of 25 pseudo-octahedral pyridylphosphinate metal complexes (Ru, Os, Rh, Ir) has been synthesised and assessed in biological systems. Each metal complex incorporates a pyridylphosphinate ligand, a monodentate halide and a capping η6-bound aromatic ligand. Solid- and solution-state analyses of two complexes reveal a structural preference for one of a possible two diastereomers. The metal chlorides hydrolyse rapidly in D2O to form a 1:1 equilibrium ratio between the aqua and chloride adducts. The pKa of the aqua adduct depends upon the pyridyl substituent and the metal but has little dependence upon the phosphinate R′ group. Toxicity was measured in vitro against non-small cell lung carcinoma H460 cells, with the most potent complexes reporting IC50 values around 50 μM. Binding studies with selected amino acids and nucleobases provide a rationale for the variation in toxicity observed within the series. Finally, an investigation into the ability of the chelating amino acid l-His to displace the phosphinate O-metal bond shows the potential for phosphinate complexes to act as prodrugs that can be activated in the intracellular environment.
- Cross, Jasmine M.,Gallagher, Natalie,Gill, Jason H.,Jain, Mohit,McNeillis, Archibald W.,Rockley, Kimberly L.,Tscherny, Fiona H.,Wirszycz, Natasha J.,Yufit, Dmitry S.,Walton, James W.
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supporting information
p. 12807 - 12813
(2016/08/24)
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- Structure-activity relationships of substituted 1-pyridyl-2-phenyl-1,2- ethanediones: Potent, selective carboxylesterase inhibitors
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Inhibition of intestinal carboxylesterases may allow modification of the pharmacokinetics/pharmacodynamic profile of existing drugs by altering half-life or toxicity. Since previously identified diarylethane-1,2-dione inhibitors are decidedly hydrophobic,
- Young, Brandon M.,Hyatt, Janice L.,Bouck, David C.,Chen, Taosheng,Hanumesh, Parimala,Price, Jeanine,Boyd, Vincent A.,Potter, Philip M.,Webb, Thomas R.
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supporting information; experimental part
p. 8709 - 8715
(2011/02/23)
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- Heteroaryl derivatives as superior ligands for nociceptin receptor ORL-1
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Novel compounds of the formula wherein R is optionally substituted heteroaryl or R1 is H or C1—C6 alkyl; and R2 and R3 are —CH3, —OCH3 or halo; or a pharmaceutically acceptable salt or solvate thereof, pharmaceutical compositions therefore, and the use of said compounds in the treatment of pain, anxiety, cough, asthma, depression and alcohol abuse are disclosed.
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