23997-94-6Relevant articles and documents
Imaging Mutant Huntingtin Aggregates: Development of a Potential PET Ligand
Prime, Michael E.,Liu, Longbin,Lee, Matt R.,Khetarpal, Vinod,Brown, Christopher J.,Johnson, Peter D.,Miranda-Azpiazu, Patricia,Chen, Xuemei,Clark-Frew, Daniel,Coe, Samuel,Davis, Randall,Dickie, Anthony,Ebneth, Andreas,Esposito, Simone,Gadouleau, Elise,Gai, Xinjie,Galan, Sebastien,Green, Samantha,Greenaway, Catherine,Giles, Paul,Halldin, Christer,Hayes, Sarah,Herbst, Todd,Herrmann, Frank,He?mann, Manuela,Jia, Zhisheng,Kiselyov, Alexander,Kotey, Adrian,Krulle, Thomas,Mangette, John E.,Marston, Richard W.,Menta, Sergio,Mills, Matthew R.,Monteagudo, Edith,Nag, Sangram,Nibbio, Martina,Orsatti, Laura,Schaertl, Sabine,Scheich, Christoph,Sproston, Joanne,Stepanov, Vladimir,Svedberg, Marie,Takano, Akihiro,Taylor, Malcolm,Thomas, Wayne,Toth, Miklós,Vaidya, Darshan,Vanr?s, Katarina,Weddell, Derek,Wigginton, Ian,Wityak, John,Mrzljak, Ladislav,Munoz-Sanjuan, Ignacio,Bard, Jonathan A.,Dominguez, Celia
, p. 8608 - 8633 (2020/09/16)
Mutant huntingtin (mHTT) protein carrying the elongated N-Terminal polyglutamine (polyQ) tract misfolds and forms protein aggregates characteristic of Huntington's disease (HD) pathology. A high-Affinity ligand specific for mHTT aggregates could serve as a positron emission tomography (PET) imaging biomarker for HD therapeutic development and disease progression. To identify such compounds with binding affinity for polyQ aggregates, we embarked on systematic structural activity studies; lead optimization of aggregate-binding affinity, unbound fractions in brain, permeability, and low efflux culminated in the discovery of compound 1, which exhibited target engagement in autoradiography (ARG) studies in brain slices from HD mouse models and postmortem human HD samples. PET imaging studies with 11C-labeled 1 in both HD mice and WT nonhuman primates (NHPs) demonstrated that the right-hand-side labeled ligand [11C]-1R (CHDI-180R) is a suitable PET tracer for imaging of mHTT aggregates. [11C]-1R is now being advanced to human trials as a first-in-class HD PET radiotracer.
Utility of Nitrogen Extrusion of Azido Complexes for the Synthesis of Nitriles, Benzoxazoles, and Benzisoxazoles
Nimnual, Phongprapan,Tummatorn, Jumreang,Thongsornkleeb, Charnsak,Ruchirawat, Somsak
, p. 8657 - 8667 (2015/09/15)
The utility of the nitrogen extrusion reaction of azido complexes, generated in situ from the corresponding aldehydes or ketones with TMSN3 in the presence of ZrCl4 or TfOH, has been described. These azido complexes could undergo three different pathways, depending on the substrates. First, azido methanolate complexes or imine diazonium ions could lead to benzisoxazole products via an intramolecular nucleophilic substitution. Second, imine diazonium ions could also undergo either the elimination of proton to provide nitrile products in good to excellent yields or an aryl migration, followed by an intramolecular nucleophilic addition, to give benzoxazole products in good yields.
IRE-1α INHIBITORS
-
Paragraph 1369; 1371; 1372, (2016/10/07)
PROBLEM TO BE SOLVED: To provide compounds which directly inhibit inositol requiring enzyme 1 (IRE-1α activity) in vitro, prodrugs, and pharmaceutically acceptable salts thereof. SOLUTION: The present invention provides a compound represented by formula (A) [R3 and R4 are H or the like; Q5-Q8, together with the benzene ring to which they are attached, form a benzofused ring, where at least one of Q5-Q8 is a heteroatom selected from N, O, and S. COPYRIGHT: (C)2016,JPOandINPIT