- Structure-based optimization of oxadiazole-based GSK-3 inhibitors
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Inhibition of glycogen synthase kinase-3 (GSK-3) induces neuroprotective effects, e.g. decreases β-amyloid production and reduces tau hyperphosphorylation, which are both associated with Alzheimer's disease (AD). The two isoforms of GSK-3 in mammalians are GSK-3α and β, which share 98% homology in their catalytic domains. We investigated GSK-3 inhibitors based on 2 different scaffolds in order to elucidate the demands of the ATP-binding pocket [1]. Particularly, the oxadiazole scaffold provided potent and selective GSK-3 inhibitors. For example, the most potent inhibitor of the present series, the acetamide 26d, is characterized by an IC50 of 2 nM for GSK-3α and 17 nM for GSK-3β. In addition, the benzodioxane 8g showed up to 27-fold selectivity for GSK-3α over GSK-3β, with an IC 50 of 35 nM for GSK-3α. Two GSK-3 inhibitors were further profiled for efficacy and toxicity in the wild-type (wt) zebrafish embryo assay to evaluate simultaneously permeability and safety.
- Lo Monte, Fabio,Kramer, Thomas,Gu, Jiamin,Brodrecht, Martin,Pilakowski, Johannes,Fuertes, Ana,Dominguez, Juan Manuel,Plotkin, Batya,Eldar-Finkelman, Hagit,Schmidt, Boris
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- Identification of glycogen synthase kinase-3 inhibitors with a selective sting for glycogen synthase kinase-α
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The glycogen synthase kinase-3 (GSK-3) has been linked to the pathogenesis of colorectal cancer, diabetes, cardiovascular disease, acute myeloid leukemia (AML), and Alzheimer's disease (AD). The debate on the respective contributions of GSK-α and GSK-3β to AD pathology and AML is ongoing. Thus, the identification of potent GSK-α-selective inhibitors, endowed with favorable pharmacokinetic properties, may elucidate the effect of GSK-α inhibition in AD and AML models. The analysis of all available crystallized GSK-3 structures provided a simplified scheme of the relevant hot spots responsible for ligand binding and potency. This resulted in the identification of novel scorpion shaped GSK-3 inhibitors. It is noteworthy, compounds 14d and 15b showed the highest GSK-α selectivity reported so far. In addition, compound 14d did not display significant inhibition of 48 out of 50 kinases in the test panel. The GSK-3 inhibitors were further profiled for efficacy and toxicity in the wild-type (wt) zebrafish embryo assay.
- Lo Monte, Fabio,Kramer, Thomas,Gu, Jiamin,Anumala, Upendra Rao,Marinelli, Luciana,La Pietra, Valeria,Novellino, Ettore,Franco, Bénédicte,Demedts, David,Van Leuven, Fred,Fuertes, Ana,Dominguez, Juan Manuel,Plotkin, Batya,Eldar-Finkelman, Hagit,Schmidt, Boris
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experimental part
p. 4407 - 4424
(2012/08/13)
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- THIAZOLE COMPOUNDS AS ACTIVATORS OF SOLUBLE GUANYLATE CYCLASE
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Disclosed are compounds of formula (I) wherein R1 and R2 are independently selected from hydrogen, halo, C1-4alkyl, C1-4alkoxy, CF3 and OCF3; -Y- represents formula (IA) R3 represents hydrogen, fluoro, chloro or C1-4alkyl; R4a and R4b each independently represent hydrogen, C1-4alkyl, C1-4alkoxy, CF3 or halo; and R5 represents a group Z-X; wherein Z is absent or represents (CH2)2 or O; and X represents formula (IB) wherein: J and L both represent CH, or one of J and L represents CH and the other represents N; when both J and L represent CH, R6 represents hydrogen, halo, CF3, C1-4alkyl or C1-4alkoxy in a meta or ortho position relative to the R7 substituent and R7 represents hydrogen, halo, CF3, OCF3, C1-4alkyl, C1-4alkoxy, CH2OH, CN, CONR8R9 or CO2H; or when one of J or L represents N, R6 represents hydrogen or halo in a meta or ortho position relative to the R7 substituent and R7 represents hydrogen, halo, CF3, C1-4alkyl, C1-4alkoxy, CH2OH, CN, CONR8R9 or CO2H; and R8 and R9 are independently selected from hydrogen and C1-4alkyl; or salts thereof which activate soluble guanylate cyclase (sGC), pharmaceutical compositions containing them, their use in medicine, and processes for their preparation.
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Page/Page column 47
(2010/04/03)
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- PYRIMIDINE DERIVATIVES AS ACTIVATORS OF SOLUBLE GUANYLATE CYCLASE
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Disclosed are compounds of formula (I) and or salts thereof which activate soluble guanylate cyclase (sGC), pharmaceutical compositions containing them, their use in the manufacture of a medicament for teating cardiovascular diseases, and processes for their preparation.
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Page/Page column 41
(2010/04/03)
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- 2,6-DISUBSTITUTED PYRIDINES AS SOLUBLE GUANYLATE CYCLASE ACTIVATORS
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Disclosed are compounds of formula (I) wherein R1 and R2 are independently selected from hydrogen, halo, CF3, C1-4alkyl and allyl; Y represents (II), (III), (IV) or (V) wherein R3 represents CF3 or C1-4alkyl; and R3a represents CF3 or C1-4alkyl.
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Page/Page column 68
(2009/07/17)
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- COMPOSITIONS AND LIQUID CRYSTALS
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The present invention relates to compounds, compositions, and methods in the field of detection of analytes. In particular to detection of viruses, cells, bacteria, lipid-membrane containing organisms, proteins, nucleic acids, carbohydrates and other biom
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Page/Page column 62-63
(2008/06/13)
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- Benzimidazole-Based fXa inhibitors with improved thrombin and trypsin selectivity
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Optimization of the benzimidazole-based fXa inhibitors for selectivity versus thrombin and trypsin was achieved by substitution on the benzimidazole ring and replacement of the naphthylamidine group. Substitution of a nitro group at the 4-position on the benzimidazole improves both potency against fXa and selectivity versus thrombin. Alternatively, replacement of the naphthylamidine with either a biphenylamidine or propenylbenzamidine not only improves fXa potency and selectivity versus thrombin, but selectivity versus trypsin as well.
- Shaw, Kenneth J.,Guilford, William J.,Griedel, Brian D.,Sakata, Steve,Trinh, Lan,Wu, Shung,Xu, Wei,Zhao, Zuchun,Morrissey, Michael M.
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p. 1311 - 1314
(2007/10/03)
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- Imidazole substituted biphenyls: A new class of highly potent and in vivo active inhibitors of P450 17 as potential therapeutics for treatment of prostate cancer
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3- And 4-imidazol-1-yl-methyl substituted biphenyl compounds (named as meta- and para-substituted compounds) were synthesized bearing additional substituents in 3'-/4'-position as inhibitors of P450 17 (17α-hydroxylase-C17,20-lyase). P450 17 is the key enzyme of androgen biosynthesis. Its inhibition is a novel therapeutic strategy for treatment of prostate cancer (PC). Twenty-nine compounds were synthesized by Ar-Mg-Br, Negishi or Suzuki aryl-aryl cross coupling and tested toward human and rat enzyme. Most of the compounds showed moderate to excellent activity against one of the enzymes (0.087 μM ≤ IC50 ≤ 7.7 μM (ketoconazole: 0.74 μM) for the human enzyme, 0.63 μM ≤ IC50 ≤ 32 μM (ketoconazole: 67 μM) for the rat enzyme). Interestingly, strong species differences were observed. In addition compounds were tested for inhibition toward P450 arom. The 3-imidazol-1-yl-methyl substituted compounds showed good inhibitory activity of P450 arom, while for the 4-substituted compounds negligible inhibition was found. For the most active group of P450 17 inhibitors, (i.e. the 4-imidazol-1-yl-methyl substituted compounds) a QSAR study was performed for inhibition of the human enzyme leading to the result that a hydrophilic substituent in 3'-/4'-position is very important. The most promising compounds (with respect to activity toward both enzymes) were tested in vivo using SD-rats for reduction of plasma testosterone concentrations 2 and 6h after single ip application. The fluorine substituted compound 8c decreased the testosterone plasma concentration to castration level (after 2h; 5 mg/kg) showing a biological half live of about 6h.
- Wachall, Bertil G.,Hector, Markus,Zhuang, Yan,Hartmann, Rolf W.
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p. 1913 - 1924
(2007/10/03)
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