- 1,4-naphthoquinone derivative, preparation method and applications thereof
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The invention relates to a 1,4-naphthoquinone derivative, a preparation method and applications thereof. According to the present invention, the 1,4-naphthoquinone derivative is firstly synthesized, has good activity in the inhibition of human colon cance
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- HEPATITIS B VIRAL ASSEMBLY EFFECTORS
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Novel assembly effector compounds having a therapeutic effect against hepatitis B viral (HBV) infection are disclosed. Assembly effector molecules described herein can lead to defective viral assembly and also may affect other viral activities associated with chronic HBV infection. Also disclosed is a process to synthesize disclosed compounds, method of treatment of HBV by administration of disclosed compounds, and use of these compounds in the manufacture of medicaments against HBV.
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- Discovery of sulfonamidebenzamides as selective apoptotic CHOP pathway activators of the unfolded protein response
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Cellular proteins that fail to fold properly result in inactive or disfunctional proteins that can have toxic functions. The unfolded protein response (UPR) is a two-tiered cellular mechanism initiated by eukaryotic cells that have accumulated misfolded p
- Flaherty, Daniel P.,Miller, Justin R.,Garshott, Danielle M.,Hedrick, Michael,Gosalia, Palak,Li, Yujie,Milewski, Monika,Sugarman, Eliot,Vasile, Stefan,Salaniwal, Sumeet,Su, Ying,Smith, Layton H.,Chung, Thomas D. Y.,Pinkerton, Anthony B.,Aub, Jeffrey,Callaghan, Michael U.,Golden, Jennifer E.,Fribley, Andrew M.,Kaufman, Randal J.
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p. 1278 - 1283
(2015/01/09)
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- Discovery and structure-activity relationship of potent and selective covalent inhibitors of transglutaminase 2 for Huntington's disease
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Tissue transglutaminase 2 (TG2) is a multifunctional protein primarily known for its calcium-dependent enzymatic protein cross-linking activity via isopeptide bond formation between glutamine and lysine residues. TG2 overexpression and activity have been found to be associated with Huntington's disease (HD); specifically, TG2 is up-regulated in the brains of HD patients and in animal models of the disease. Interestingly, genetic deletion of TG2 in two different HD mouse models, R6/1 and R6/2, results in improved phenotypes including a reduction in neuronal death and prolonged survival. Starting with phenylacrylamide screening hit 7d, we describe the SAR of this series leading to potent and selective TG2 inhibitors. The suitability of the compounds as in vitro tools to elucidate the biology of TG2 was demonstrated through mode of inhibition studies, characterization of druglike properties, and inhibition profiles in a cell lysate assay.
- Prime, Michael E.,Andersen, Ole A.,Barker, John J.,Brooks, Mark A.,Cheng, Robert K. Y.,Toogood-Johnson, Ian,Courtney, Stephen M.,Brookfield, Frederick A.,Yarnold, Christopher J.,Marston, Richard W.,Johnson, Peter D.,Johnsen, Siw F.,Palfrey, Jordan J.,Vaidya, Darshan,Erfan, Sayeh,Ichihara, Osamu,Felicetti, Brunella,Palan, Shilpa,Pedret-Dunn, Anna,Schaertl, Sabine,Sternberger, Ina,Ebneth, Andreas,Scheel, Andreas,Winkler, Dirk,Toledo-Sherman, Leticia,Beconi, Maria,MacDonald, Douglas,Mu?oz-Sanjuan, Ignacio,Dominguez, Celia,Wityak, John
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p. 1021 - 1046
(2012/04/10)
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- TRANSGLUTAMINASE TG2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE THEREOF
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Certain compounds and pharmaceutically acceptable salts are provided herein. Also provided are pharmaceutical compositions comprising at least one compound or pharmaceutically acceptable salt therein and one or more pharmaceutically acceptable vehicle. Methods of treating patients suffering from certain disease states responsive to the inhibition of transglutaminase TG2 activity are described. These disease states include neurodegenerative disorders such as Huntington's disease. Also described are methods of treatment include administering at least one compound or pharmaceutically acceptable salt thereof as a single active agent or administering at least one compound or pharmaceutically acceptable salt thereof in combination with one or more other therapeutic agents.
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- THIAZOLE INHIBITORS TARGETING RESISTANT AND KINASE MUTATIONS
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A compound is provided, having the general structure (A): wherein A is an aryl or heteroaryl group, Y is a hydrophobic linking moiety, and L is a substitutent. The compound (A) can be used for treatment of various angiogenic-associated or hematologic disorders, such as myeloproliferative disorders in patients who do not respond to kinase-inhibition therapy that comprises administering currently used medications.
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Page/Page column 47
(2010/11/27)
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- DIAMINOPYRIMIDINECARBOXA MIDE DERIVATIVE
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A compound which may be used for the prevention or treatment of respiratory diseases in which STAT 6 is concerned, particularly asthma, chronic obstructive pulmonary disease and the like is provided. A pyrimidine derivative or a salt thereof, which has an arylamino or arylethylamino group which may be substituted with a specified substituent, at the 2-position, amino group substituted with benzyl group or the like, at the 4-position, and carbamoyl group which may be substituted, at the 5-position, is provided.
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Page/Page column 22
(2008/06/13)
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- Structure-based design of lipophilic quinazoline inhibitors of thymidylate synthase
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To develop novel lipophilic thymidylate synthase (TS) inhibitors, the X- ray structure of Escherichia coli TS in ternary complex with FdUMP and the inhibitor 10-propargyl-5,8-dideazafolic acid (CB3717) was used as a basis for structure-based design. A total of 31 novel lipophilic TS inhibitors, lacking a glutamate residue, were synthesized; 26 of them had in common a N-((3,4- dihydro-2-methyl-6-quinazolinyl)methyl)-N-prop-2-ynylaniline structure in which the aniline was appropriately substituted with simple lipophilic substituents either in position 3 or 4, or in both. Compounds were tested for their inhibition of E. coli TS and human TS and also for their inhibition of the growth in tissue culture of a murine leukemia, a human leukemia, and a thymidine kinase-deficient human adenocarcinoma. The crystal structures of five inhibitors complexed with E. coli TS were determined. Five main conclusions are drawn from this study. (i) A 3-substituent such as CF3, iodo, or ethynyl enhances binding by up to 1 order of magnitude and in the case of CF3 was proven to fill a nearby pocket in the enzyme. (ii) A simple strongly electron-withdrawing substituent such as NO2 or CF3SO2 in the 4- position enhances binding by 2 orders of magnitude; it is hypothesized that the transannular dipole so induced interacts favorably with the protein. (iii) Attempts to combine the enhancements of i and ii in the same molecule were generally unsuccessful. (iv) A 4-C6H5SO2 substituent provided both electron withdrawal and a van der Waal's interaction of the phenyl group with a hydrophobic surface at the mouth of the active site. The inhibition (K(is) = 12 nM) of human TS by this compound, 7n, showed that C6H5SO2 provided virtually as much binding affinity as the CO-glutamate which it had replaced. (v) The series of compounds were poorly water soluble, and also the potent TS inhibition shown by several of them did not translate into good cytotoxicity. Compounds with large cyclic groups linked to position 4 by an SO or SO; group did, however, have IC50's in the range 1-5 μM. Of these, 4-(N-((3,4- dihydro-2-methyl-6-quinazolinyl)methyl)-N-prop-2-ynylamino)phenyl phenyl sulfone, 7n, had IC50's of about 1 μM and was chosen for further elaboration.
- Jones, Terence R.,Varney, Michael D.,Webber, Stephen E.,Lewis, Kathleen K.,Marzoni, Gifford P.,Palmer, Cindy L.,Kathardekar, Vinit,Welsh, Katharine M.,Webber, Stephanie,Matthews, David A.,Appelt, Krzysztof,Smith, Ward W.,Janson, Cheryl A.,Villafranca,Bacquet, Russell J.,Howland, Eleanor F.,Booth, Carol L. J.,Herrmann, Steven M.,Ward, Robert W.,White, Jennifer,Moomaw, Ellen W.,Bartlett, Charlotte A.,Morse, Cathy A.
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p. 904 - 917
(2007/10/03)
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