955112-52-4Relevant academic research and scientific papers
SUBSTITUTED 1,2,3-TRIAZOLES AS NR2B-SELECTIVE NMDA MODULATORS
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Page/Page column 128; 129, (2017/09/07)
Substituted 1,2,3-triazoles as NR2B receptor ligands. Such compounds may be used in NR2B receptor modulation and in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by NR2B receptor activity.
Discovery of Novel Dot1L Inhibitors through a Structure-Based Fragmentation Approach
Chen, Chao,Zhu, Hugh,Stauffer, Frédéric,Caravatti, Giorgio,Vollmer, Susanne,Machauer, Rainer,Holzer, Philipp,M?bitz, Henrik,Scheufler, Clemens,Klumpp, Martin,Tiedt, Ralph,Beyer, Kim S.,Calkins, Keith,Guthy, Daniel,Kiffe, Michael,Zhang, Jeff,Gaul, Christoph
supporting information, p. 735 - 740 (2016/08/24)
Oncogenic MLL fusion proteins aberrantly recruit Dot1L, a histone methyltransferase, to ectopic loci, leading to local hypermethylation of H3K79 and misexpression of HoxA genes driving MLL-rearranged leukemias. Inhibition of the methyltransferase activity of Dot1L in this setting is predicted to reverse aberrant H3K79 methylation, leading to repression of leukemogenic genes and tumor growth inhibition. In the context of our Dot1L drug discovery program, high-throughput screening led to the identification of 2, a weak Dot1L inhibitor with an unprecedented, induced pocket binding mode. A medicinal chemistry campaign, strongly guided by structure-based consideration and ligand-based morphing, enabled the discovery of 12 and 13, potent, selective, and structurally completely novel Dot1L inhibitors.
High-efficacy 5-HT1A agonists for antidepressant treatment: A renewed opportunity
Maurel, Jean Louis,Autin, Jean-Marie,Funes, Philippe,Newman-Tancredi, Adrian,Colpaert, Francis,Vacher, Bernard
, p. 5024 - 5033 (2008/03/13)
We report the discovery of novel 5-HT1A receptor agonists and describe the process that led to the antidepressant candidate 9 (F 15599). 9 has nanomolar affinity for 5-HT1A binding sites and is over 1000-fold selective with respect to the other 5-HT1 receptor subtypes, 5-HT2-7 receptor families, and also numerous GPCRs, transporters, ion channels, and enzymes. In a cellular model of signal transduction, 9 activates h5-HT1A receptors with an efficacy superior to that of the prototypical 5-HT1A agonist (±)-8-OH-DPAT and comparators undergoing clinical trials. After acute oral administration in rats, 9 totally reverses immobility in the forced swimming test and produces behaviors characteristic of 5-HT1A receptor activation. However, these effects occurred at widely separated doses, suggesting that 9 discriminates between distinct populations of 5-HT1A receptors. While the clinical relevance of these observations is still unknown, this opens new perspectives for the treatment of depressive disorders.
