- A Copper Complex of a Thiosemicarbazone-Pyridylhydrazone Ligand Containing a Vinylpyridine Functional Group as a Potential Imaging Agent for Amyloid-β Plaques
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Complexes containing positron-emitting radionuclides of copper have the potential to be of use for diagnostic imaging with positron emission tomography. Alzheimer's disease is characterised by the presence of amyloid-β plaques in the brain. A new thiosemicarbazone-pyridyl hydrazone tetradentate ligand with a pyridyl-4-vinylpyridine functional group was prepared with the aim of making a copper complex that binds to amyloid-β plaques to assist in the diagnosis of Alzheimer's disease. The ligand forms a charge neutral complex with copper(ii) that was characterised by X-ray crystallography and the electrochemical behaviour of the complex was investigated by cyclic voltammetry. The new ligand can be radiolabelled with positron-emitting copper-64 at room temperature in excellent radiochemical yields. The new complex interacts with synthetic amyloid-β fibrils and binds amyloid-β plaques present in post-mortem Alzheimer's disease brain tissue.
- McInnes, Lachlan E.,Noor, Asif,Roselt, Peter D.,McLean, Catriona A.,White, Jonathan M.,Donnelly, Paul S.
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- Synthesis of a Non-Heme Template for Attaching Four Peptides: An Approach to Artificial Iron (II)-Containing Peroxidases
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We are developing all-synthetic model cofactor-protein complexes in order to define the parameters controlling non-natural cofactor activity. The long-term objective is to establish the theoretical and practical basis for designing novel enzymes. A non-heme pentadentate ligand (N4Py) is being developed as a template for the site-specific attachment of a designed four-helix bundle. Previously, we attached two unprotected peptides via CH 2Cl handles to N4Py. In the presence of hydrogen peroxide, the iron(II) complex of this ligand (2a) generates an FeIIIOOH intermediate (3a) that can oxidize a wide variety of organic compounds. Here, we describe the synthesis of 27, a N4Py derivative in which four three-carbon spacers have been introduced, and show that four copies of an unprotected, single-cysteine peptide can be coupled via a thioether linkage to the ligand. In addition, a divergent synthesis route to tetrabromide ligand lb has also been developed, providing the opportunity to prepare alternative pentadentate ligands efficiently by four cross-coupling reactions on a single molecule. Also, two of the four bromides of lb can be selectively addressed by magnesium-bromide exchange.
- Van Den Heuvel, Marco,Van Den Berg, Tieme A.,Kellogg, Richard M.,Choma, Christin T.,Feringa, Ben L.
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- CDK4/6 INHIBITORS AND USE THEREOF
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The present disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt, a solvate, a stereoisomer, or tautomer thereof, a pharmaceutical composition comprising a compound of formula (A) or formula (B), and any subgenera thereof, and use of said compounds and compositions thereof, wherein R1, R2, R3a, R3b, R5, R6, X1, X2, Y and n are described herein.
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Paragraph 731-733
(2019/03/05)
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- Rhenium and technetium complexes of thioamide derivatives of pyridylhydrazine that bind to amyloid-β plaques
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Abstract: Age-associated deposition of amyloid-β in cerebral blood vessels, a condition referred to as cerebral amyloid angiopathy, can contribute to stroke and dementia. This research aimed to design new radioactive technetium-99?m complexes that bind to amyloid-β plaques that have the potential to assist in diagnosis of cerebral amyloid angiopathy using single-photon-emitted computed tomography (SPECT) imaging. Six new pyridylthiosemicarbazide ligands containing either benzofuran or styrylpyridyl functional groups that are known to selectively bind to amyloid plaques were prepared. Non-radioactive isotopes of technetium are not available so rhenium was used as a surrogate for exploratory chemistry. The new ligands were used to prepare well-defined [Re-oxo]3+ complexes where two pyridylthiosemicarbazide ligands were coordinated to a single metal ion to give bivalent complexes with two amyloid-β targeting functional groups. The interaction of the [Re-oxo]3+ complexes with synthetic amyloid-β1-42 and with amyloid plaques in human brain tissue was investigated. Two ligands were selected to develop methods to prepare their [99mTc-oxo]3+ complexes at the tracer level. These technetium-99?m complexes are likely to be isostructural to their rhenium-oxo analogues.
- Fletcher, Scott P.,Noor, Asif,Hickey, James L.,McLean, Catriona A.,White, Jonathan M.,Donnelly, Paul S.
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p. 1139 - 1151
(2018/07/13)
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- Benzimidazole derivatives, preparation methods and uses theirof
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The present invention relates to benzimidazole compounds useful in treating for protein kinase-associated disorders. There is also a need for compounds useful in the treatment or prevention of one or more symptoms of cancer, transplant rejections. Furthermore, there is a need for methods for modulating the activity of protein kinases, such as CDK4 and/or CDK6, using the compounds provided herein.
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Page/Page column 31
(2018/12/01)
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- Synthesis of Oxorhenium(V) and Oxotechnetium(V) Complexes That Bind to Amyloid-β Plaques
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Alzheimer's disease is characterized by the presence of amyloid plaques in the brain. The primary constituents of the plaques are aggregated forms of the amyloid-β (Aβ) peptide. With the goal of preparing technetium-99m complexes that bind to Aβ plaques with the potential to be diagnostic imaging agents for Alzheimer's disease, new tetradentate ligands capable of forming neutral and lipophilic complexes with oxotechentium(V) and oxorhenium(V) were prepared. Nonradioactive isotopes of technetium are not available so rhenium was used as a surrogate for exploratory chemistry. Two planar tetradentate N3O ligands were prepared that form charge-neutral complexes with oxorhenium(v) as well as a ligand featuring a styrylpyridyl functional group designed to bind to Aβ plaques. All three ligands formed complexes with oxorhenium(V), and each complex was characterized by NMR spectroscopy, mass spectrometry, and X-ray crystallography. The oxorhenium(V) complex with a styrylpyridyl functional group binds to Aβ plaques present in post-mortem human brain tissue. The chemistry was extrapolated to technetium-99m at the tracer level for two of the ligands. The resulting oxotechnetium(V) complexes were sufficiently lipophilic and charge-neutral to suggest that they have the potential to cross the blood-brain barrier but exhibited modest stability with respect to exchange with histidine. The chemistry presented here identifies a strategy to integrate styrylpyridyl functional groups into tetradentate ligands capable of forming complexes with [M=O]3+ cores (M = Re or Tc).
- Hayne, David J.,White, Jonathan M.,McLean, Catriona A.,Villemagne, Victor L.,Barnham, Kevin J.,Donnelly, Paul S.
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p. 7944 - 7953
(2016/08/24)
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- Hydroxypurine compound and use thereof
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The invention discloses a hydroxypurine compound and a use of the hydroxypurine compound as a PDE2 or TNFa inhibitor and concretely discloses a compound shown in the formula (I) and its tautomer or pharmaceutically acceptable salt.
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- INHIBITORS OF PROTEIN TYROSINE KINASE ACTIVITY
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The present invention provides new compounds and methods for treating a disease responsive to inhibition of kinase activity, for example a disease responsive to inhibition of protein tyrosine kinase activity, for example a disease responsive to inhibition of protein tyrosine kinase activity of growth factor receptors, for example a disease responsive to inhibition of receptor type tyrosine kinase signaling, or for example, a disease responsive to inhibition of VEGF receptor signaling.
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Paragraph 000299-000300
(2013/04/13)
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- METALLOENZYME INHIBITOR COMPOUNDS
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The instant invention describes compounds having metalloenzyme modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by such metalloenzymes.
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Page/Page column 105-108
(2013/02/28)
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- Synthesis and optoelectronic properties of a carbazole-modified platinum(ii) complex in polymer light-emitting devices
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To improve opto-electronic properties and efficiently suppress excimer emission, a phenylpyridine (ppy)-based platinum(ii) complex (C 16OCz-ppy)Pt(acac) was synthesized and characterized, where C 16OCz-ppy is a 2-phenylpyridine deriv
- Luo, Jian,Liu, Yu,Shi, Danyan,Wang, Yafei,Zhang, Zhiyong,Yu, Junting,Lei, Gangtie,Chen, Qing,Li, Jianmin,Deng, Xianping,Zhu, Weiguo
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scheme or table
p. 1074 - 1081
(2012/03/22)
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- Design and synthesis of active site inhibitors of the human farnesyl pyrophosphate synthase: Apoptosis and inhibition of ERK phosphorylation in multiple myeloma cells
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Human farnesyl pyrophosphate synthase (hFPPS) controls intracellular levels of FPP and post-translational prenylation of small GTPase proteins, which are essential for cell signaling and cell proliferation. Clinical investigations provide evidence that N-BP inhibitors of hFPPS are disease modifying agents that improve survival of multiple myeloma (MM) patients via mechanisms unrelated to their skeletal effects. A new series of N-BPs was designed that interact with a larger portion of the GPP subpocket, as compared to the current therapeutic drugs, and rigidify the 364KRRK367 tail of hFPPS in the closed conformation in the absence of IPP. An analogue of this series was used to demonstrate inhibition of the intended biological target, resulting in apoptosis and down-regulation of ERK phosphorylation in human MM cell lines.
- Lin, Yih-Shyan,Park, Jaeok,De Schutter, Joris W.,Huang, Xian Fang,Berghuis, Albert M.,Sebag, Michael,Tsantrizos, Youla S.
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experimental part
p. 3201 - 3215
(2012/05/20)
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- Protein-inorganic array construction: Design and synthesis of the building blocks
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Herein we describe the design and synthesis of the first series of di-functional ligands for the directed construction of inorganic-protein frameworks. The synthesized ligands are composed of a metal-ion binding moiety (terpyridine-based) conjugated to an epoxysuccinyl peptide, known to covalently bind active cysteine proteases through the active-site cysteine. We explore and optimize two different conjugation chemistries between the di-functionalized metal-ion ligand and the epoxysuccinyl-containing peptide moiety: peptide-bond formation (with limited success) and Cu'-catalysed click chemistry (with good results). Further, the complexation of the synthesized ligands with Fe" and NiII" ions is investigated: the di-functional ligands are confirmed to behave similarly to the parent terpyridine. As designed, the peptidic moiety does not interfere with the complexation reaction, in spite of the presence of two triazole rings that result from the click reaction. ES-MS together with NMR and UV/Vis stud-ies establish the structure, the stoichiometry of the complexation reactions, as well as the conditions under which chemically sensitive peptide-containing polypyridine ligands can undergo the self-assembly process. These results establish the versatility of our approach and open the way to the synthesis of di-functional ligands containing more elaborated polypyridine ligands as well as affinity labels for different enzyme families. As such, this paper is the first step towards the construction of robust supramolecular species that cover a size-regime and organization level previously unexplored.
- Bogdan, Niculina D.,Matache, Mihaela,Meier, Veronika M.,Dobrotae, Cristian,Dumitru, Ioana,Roiban, Gheorghe D.,Funeriu, Daniel P.
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experimental part
p. 2170 - 2180
(2010/07/05)
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- BICYCLIC NITROIMIDAZOLES COVALENTLY LINKED TO SUBSTITUTED PHENYL OXAZOLIDINONES
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The current invention provides a series of bicyclic nitroimidazole- substituted phenyl oxazolidinones in which a bicyclic nitroimidazole pharmacophore is covalently bonded to a phenyl oxazolidinone, their pharmaceutical compositions, and the method of use of the compositions for prevention and treatment of bacterial infections. The bicyclic nitroimidazole-substituted phenyl oxazolidinones possess surprising antibacterial activity against wild- type and resistant strains of pathogens, and are therefore useful for the prevention, control and treatment of a number of human and veterinary bacterial infections caused by these pathogens, such as Mycobacterium tuberculosis.
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(2009/10/22)
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- 4-(PYRIDIN-3-YL)-2-(PYRIDIN-2-YL)-1,2-DIHYDRO-3H-PYRAZOL-3-ONE DERIVATIVES AS SPECIFIC HIF-PROLYL-4-HYDROXYLASE INHIBITORS FOR TREATING CARDIOVASCULAR AND HAEMATOLOGICAL DISEASES
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The object of the invention is to provide new compounds which can be used for the treatment of diseases, in particular cardiovascular and haematological diseases. The present invention describes compounds which act as specific HIF-prolyl-4-hydroxylase inhibitors and which, because of this specific in vivo action mechanism, induce HIF target genes, such as erythropoietin, and the thus produced biological processes, such as erythropoiesis, after parenteral or oral administration. The present invention relates to compounds having the general formula (I), in which A stands for CH or N, R1 stands for a substituent selected from the group formed by (C1-C6)-alkyl, trifluoromethyl, halogen, cyano, nitro, hydroxy, (C1-C6)-alkoxy, amino, (C1-C6)-alkoxycarbonyl, hydroxycarbonyl and C(=O)-NH-R4; R2 stands for a substituent selected from the group formed by halogen, cyano, nitro, (C1-C6)-alkyl, trifluoromethyl, hydroxy, (C1-C6)-alkoxy, trifluoromethoxy, amino, hydroxycarbonyl and C(=O)-NH-R8; m equals 0, 1 or 2; n equals 0, 1, 2 or 3, it being possible for these meanings to be the same or different when R1 or R2 occurs multiple times; and R3 stands for hydrogen, (C1-C6)-alkyl or (C3-C7)-cycloalkyl. The invention also relates to the salts, solvates, and salt solvates of these compounds.
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Page/Page column 29-30
(2008/06/13)
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- 2-IMINOPYRROLIDINE DERIVATES
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A 2-iminopyrrolidine derivative represented by the formula: {wherein ring B represents a benzene ring, pyridine ring, etc.; R101 - R103 represent hydrogen, halogen, C1-6 alkyl, etc.; R5 represents hydrogen, C1-6 alkyl, C1-6 alkoxy-C1-6 alkyl, etc.; R6 represents hydrogen, C1-6 alkyl, C1-6 alkyloxycarbonyl, etc.; Y1 represents a single bond, -CH2-, etc.; Y2 represents a single bond, -CO-, etc.; and Ar represents hydrogen, a group represented by the formula: [wherein R10-R14 represent hydrogen, C1-6 alkyl, hydroxyl, C1-6 alkoxy, etc.; and R11 and R12 or R12 and R13 may bond together to form a 5- to 8-membered heterocyclic ring], etc.}, or a salt thereof.
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Page 143-144
(2008/06/13)
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- Inhibitors of prenyl-protein transferase
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The present invention is directed to macrocyclic compounds which inhibit prenyl-protein transferase and the prenylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invent
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- INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
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The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.
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- Aryl substituted dibenzoxazepine compounds, pharmaceutical compositions and methods of use
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The present invention provides substituted dibenzoxazepine compounds of Formula I: STR1 which are useful as analgesic agents for the treatment of pain, and for the treatment of prostaglandin E2 -mediated diseases, pharmaceutical compositions comprising a therapeutically-effective amount of a compound of Formula I in combination with a pharmaceutically-acceptable carrier, a method for eliminating or ameliorating pain in an animal, and a method for treating prostaglandin E2 -mediated diseases in an animal, comprising administering a therapeutically-effective amount of a compound of Formula I to the animal.
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- SUBSTITUTED BENZIMIDAZOLES AND QUINAZOLINES AS ANTIHYPERTENSIVES
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There are disclosed compounds of the formula STR1 wherein R 1 is STR2 R 2 is STR3 wherein X is STR4 wherein R. sup.5 is hydrogen, alkyl of 1-6 carbon atoms, benzyl, triphenylmethyl, or Sn(alkyl of 1-6 carbon atoms) 3 ;n is 1 to 3;Y is STR5 wherein R 3 is hydrogen, perfluoro alkyl of 1-6 carbon atoms, trifluoromethylalkyl of 1-6 carbon atoms, or alkyl of 1-6 carbon atoms; and R 4 is hydrogen or alkyl of 1-6 carbon atoms; with the proviso that when R 1 is STR6 then R. sup.2 cannot be STR7 wherein X is as defined above; and the pharmaceutically acceptable salts thereof, which by virtue of their ability to antagonize angiotensin II are useful for the treatment of hypertension and congestive heart-failure.
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- Pyridopyrimidine Angiotensin II Antagonists
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A series of pyridopyrimidine angiotensin II (A II) antagonists was synthesized and tested for antagonism of A II. Compounds with a biphenyltetrazole pharmacophore and small alkyl groups at the 2- and 4-positions of the pyridopyrimidine ring were found to be the most potent in an AT1 receptor binding assay and in blocking the A II pressor response in anesthetized, ganglion-blocked A II-infused rats. 5,8-Dihydro-2,4-dimethyl-8--4-yl)methyl>pyridopyrimidin-7(6H)-one (4a) was one of the more potent compounds in the binding assay and was the most efficacious compound in the A II-infused rat model. Further study of 4a in Goldblatt (2K-1C) rats showed the compound to have oral bioavailability and to be an efficacious and potent compound in a high renin form of hypertension.
- Ellingboe, John W.,Antane, Madelene,Nguyen, Thomas T.,Collini, Michael D.,Antane, Schuyler,et al.
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p. 542 - 550
(2007/10/02)
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- SUBSTITUTED PYRROLOPYRIMIDINES, AZEPINOPYRIMIDINES AND PYRIDOPYRIMIDINES USEFUL AS ANGIOTENSIN II ANTAGONISTS
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This invention relates to pyrrolo-, pyrido-, azepino-, and azocinopyrimidines of the general formula I STR1 wherein R 1, R. sup.2, R 3, and R 4 are independently H, lower alkyl containing 1 to 6 carbon atoms, or perfluoroalkyl containing 1 to 6 carbon atoms; R. sup.5 is H or when n is 1 R 5 taken together with R 3 comprises a double bond; n is 0 to 1; p is 0 to 2; m is 0 to 3; Ar 1 is STR2 wherein W is H, lower alkyl containing 1 to 6 carbon atoms, halogen, hydroxy, or lower alkoxy containing 1 to 6 carbon atoms; Ar 2 is STR3 wherein X is STR4 wherein R. sup.6 is H, tert-butyl, tri-n-butylstannyl, or triphenylmethyl; and the pharmaceutically acceptable salts thereof which by virtue of their ability to antagonize angiotensin II are useful for the treatment of hypertension, congestive heart failure, and restenosis. The compounds are also useful for reducing lipid levels in the blood plasma and are thus useful for treating hyperlipidemia and hypercholesterolemia. Also disclosed are processes for the production of said compounds and pharmaceutical compositions containing said compounds.
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- SUBSTITUTED PYRRIDOPYRIMIDINES USEFUL AS ANGIOTENSIN II ANTAGONISTS
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This invention relates to pyrrolo-, pyrido-, azepino-, and azocinopyrimidines of the general formula I STR1 useful for treating hypertension and congestive heart failure, to pharmaceutical compositions, and to methods for production thereof.
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