132038-28-9Relevant articles and documents
Discovery of Isonicotinamides as Highly Selective, Brain Penetrable, and Orally Active Glycogen Synthase Kinase-3 Inhibitors
Luo, Guanglin,Chen, Ling,Burton, Catherine R.,Xiao, Hong,Sivaprakasam, Prasanna,Krause, Carol M.,Cao, Yang,Liu, Nengyin,Lippy, Jonathan,Clarke, Wendy J.,Snow, Kimberly,Raybon, Joseph,Arora, Vinod,Pokross, Matt,Kish, Kevin,Lewis, Hal A.,Langley, David R.,Macor, John E.,Dubowchik, Gene M.
, p. 1041 - 1051 (2016/02/23)
GSK-3 is a serine/threonine kinase that has numerous substrates. Many of these proteins are involved in the regulation of diverse cellular functions, including metabolism, differentiation, proliferation, and apoptosis. Inhibition of GSK-3 may be useful in treating a number of diseases including Alzheimer's disease (AD), type II diabetes, mood disorders, and some cancers, but the approach poses significant challenges. Here, we present a class of isonicotinamides that are potent, highly kinase-selective GSK-3 inhibitors, the members of which demonstrated oral activity in a triple-transgenic mouse model of AD. The remarkably high kinase selectivity and straightforward synthesis of these compounds bode well for their further exploration as tool compounds and therapeutics.
Exploration of the structure-activity relationship of the diaryl anilide class of ligands for translocator protein - Potential novel positron emitting tomography imaging agents
Wadsworth, Harry,Jones, Paul A.,Chau, Wai-Fung,Durrant, Clare,Morisson-Iveson, Veronique,Passmore, Joanna,O'Shea, Dennis,Wynn, Duncan,Khan, Imtiaz,Black, Andrew,Avory, Michelle,Trigg, William
, p. 5795 - 5800,6 (2020/07/30)
A series of novel ligands based on the diaryl anilide (DAA) class of translocator protein (TSPO) ligands was synthesised and evaluated as potential positron emitting tomography (PET) ligands for imaging TPSO in vivo. Fluorine-18 labelling of the molecules was achieved using direct radiolabelling or synthon based labelling approaches. Several of the ligands prepared have promising profiles as potential TSPO PET imaging ligands and will be evaluated further as potential clinical imaging agents.
Synthesis and evaluation in monkey of two sensitive 11C-labeled aryloxyanilide ligands for imaging brain peripheral benzodiazepine receptors in vivo
Briard, Emmanuelle,Zoghbi, Sami S.,Imaizumi, Masao,Gourley, Jonathan P.,Shetty, H. Umesha,Hong, Jinsoo,Cropley, Vanessa,Fujita, Masahiro,Innis, Robert B.,Pike, Victor W.
, p. 17 - 30 (2008/09/18)
We sought to develop 11C-labeled ligands for sensitive imaging of brain peripheral benzodiazepine receptors (PBR) in vivo. Two aryloxyanilides with high affinity for PBR were identified and synthesized, namely, N-acetyl-N-(2-methoxycarbonylbenzyl)-2-phenoxyaniline (3, PBR01) and N-(2-methoxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamide (10, PBR28). 3 was hydrolyzed to 4, which was esterified with [11C]iodomethane to provide [11C]3. The O-desmethyl analogue of 10 was converted into [11C]10 with [11C]iodomethane. [11C]3 and [11C]10 were each injected into monkey to assess their brain kinetics with positron emission tomography (PET). After administration of either radioligand there was moderately high brain uptake of radioactivity. Receptor blocking and displacement experiments showed that a high proportion of this radioactivity was bound specifically to PBR. In monkey and rat, 3 and 10 were rapidly metabolized by ester hydrolysis and N-debenzylation, respectively, each to a single polar radiometabolite. [11C]3 and [11C]10 are effective for imaging PBR in monkey brain. [11C]10 especially warrants further evaluation in human subjects.
