953894-91-2Relevant academic research and scientific papers
Discovery and structure-activity relationship of potent and selective covalent inhibitors of transglutaminase 2 for Huntington's disease
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
, p. 1021 - 1046 (2012/04/10)
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.
TRANSGLUTAMINASE TG2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE THEREOF
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, (2011/06/16)
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.
