61500-87-6Relevant articles and documents
Synthesis and pharmacological studies at the Gly/NMDA, AMPA and Kainate receptors of new oxazolo[4,5-c]quinolin-4-one derivatives bearing different substituents at position-2 and on the fused benzo ring
Calabri, Francesca Romana,Colotta, Vittoria,Catarzi, Daniela,Varano, Flavia,Lenzi, Ombretta,Filacchioni, Guido,Costagli, Chiara,Galli, Alessandro
, p. 897 - 907 (2005)
The synthesis and biological evaluation at the Gly/NMDA, AMPA and Kainate receptors of new oxazolo[4,5-c]quinolin-4-one derivatives are reported. Different substituents were introduced at the 2-position (mercapto, carbonyl and methyl groups) and on the fu
Discovery of Icenticaftor (QBW251), a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator with Clinical Efficacy in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease
Grand, Darren Le,Gosling, Martin,Baettig, Urs,Bahra, Parmjit,Bala, Kamlesh,Brocklehurst, Cara,Budd, Emma,Butler, Rebecca,Cheung, Atwood K.,Choudhury, Hedaythul,Collingwood, Stephen P.,Cox, Brian,Danahay, Henry,Edwards, Lee,Everatt, Brian,Glaenzel, Ulrike,Glotin, Anne-Lise,Groot-Kormelink, Paul,Hall, Edward,Hatto, Julia,Howsham, Catherine,Hughes, Glyn,King, Anna,Koehler, Julia,Kulkarni, Swarupa,Lightfoot, Megan,Nicholls, Ian,Page, Christopher,Pergl-Wilson, Giles,Popa, Mariana Oana,Robinson, Richard,Rowlands, David,Sharp, Tom,Spendiff, Matthew,Stanley, Emily,Steward, Oliver,Taylor, Roger J.,Tranter, Pamela,Wagner, Trixie,Watson, Hazel,Williams, Gareth,Wright, Penny,Young, Alice,Sandham, David A.
, p. 7241 - 7260 (2021/06/28)
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel are established as the primary causative factor in the devastating lung disease cystic fibrosis (CF). More recently, cigarette smoke exposure has been shown to be asso
Halogen-substituted anthranilic acid derivatives provide a novel chemical platform for androgen receptor antagonists
Roell, Daniela,R?sler, Thomas W.,Hessenkemper, Wiebke,Kraft, Florian,Hauschild, Monique,Bartsch, Sophie,Abraham, Tsion E.,Houtsmuller, Adriaan B.,Matusch, Rudolf,van Royen, Martin E.,Baniahmad, Aria
, p. 59 - 70 (2019/02/01)
Androgen receptor (AR) antagonists are used for hormone therapy of prostate cancer (PCa). However resistance to the treatment occurs eventually. One possible reason is the occurrence of AR mutations that prevent inhibition of AR-mediated transactivation by antagonists. To offer in future more options to inhibit AR signaling, novel chemical lead structures for new AR antagonists would be beneficial. Here we analyzed structure-activity relationships of a battery of 36 non-steroidal structural variants of methyl anthranilate including 23 synthesized compounds. We identified structural requirements that lead to more potent AR antagonists. Specific compounds inhibit the transactivation of wild-type AR as well as AR mutants that render treatment resistance to hydroxyflutamide, bicalutamide and the second-generation AR antagonist enzalutamide. This suggests a distinct mode of inhibiting the AR compared to the clinically used compounds. Competition assays suggest binding of these compounds to the AR ligand binding domain and inhibit PCa cell proliferation. Moreover, active compounds induce cellular senescence despite inhibition of AR-mediated transactivation indicating a transactivation-independent AR-pathway. In line with this, fluorescence resonance after photobleaching (FRAP) - assays reveal higher mobility of the AR in the cell nuclei. Mechanistically, fluorescence resonance energy transfer (FRET) - assays indicate that the amino-carboxy (N/C)-interaction of the AR is not affected, which is in contrast to known AR-antagonists. This suggests a mechanistically novel mode of AR-antagonism. Together, these findings indicate the identification of a novel chemical platform as a new lead structure that extends the diversity of known AR antagonists and possesses a distinct mode of antagonizing AR-function.
