27866-64-4Relevant academic research and scientific papers
Development and crystallography-aided SAR studies of multifunctional BuChE inhibitors and 5-HT6R antagonists with β-amyloid anti-aggregation properties
Brazzolotto, Xavier,Bucki, Adam,Gobec, Stanislav,Knez, Damijan,Latacz, Gniewomir,Malawska, Barbara,Mordyl, Barbara,Siwek, Agata,Walczak, Maria,Wichur, Tomasz,?niecikowska, Joanna,Góral, Izabella,G?uch-Lutwin, Monika,Godyń, Justyna,Juki?, Marko,Ko?aczkowski, Marcin,Sa?at, Kinga,Wi?ckowska, Anna
, (2021/09/15)
The lack of an effective treatment makes Alzheimer's disease a serious healthcare problem and a challenge for medicinal chemists. Herein we report interdisciplinary research on novel multifunctional ligands targeting proteins and processes involved in the development of the disease: BuChE, 5-HT6 receptors and β-amyloid aggregation. Structure-activity relationship analyses supported by crystallography and docking studies led to the identification of a fused-type multifunctional ligand 50, with remarkable and balanced potencies against BuChE (IC50 = 90 nM) and 5-HT6R (Ki = 4.8 nM), and inhibitory activity against Aβ aggregation (53% at 10 μM). In in vitro ADME-Tox and in vivo pharmacokinetic studies compound 50 showed good stability in the mouse liver microsomes, favourable safety profile and brain permeability with the brain to plasma ratio of 6.79 after p.o. administration in mice, thus being a promising candidate for in vivo pharmacology studies and a solid foundation for further research on effective anti-AD therapies.
LYSYL OXIDASE-LIKE 2 INHIBITORS AND USES THEREOF
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Paragraph 00365, (2016/09/26)
Described herein are compounds that are LOXL2 inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with LOXL2 activity.
Indole inhibitors of human nonpancreatic secretory phospholipase A2. 3. Indole-3-glyoxamides
Draheim, Susan E.,Bach, Nicholas J.,Dillard, Robert D.,Berry, Dennis R.,Carlson, Donald G.,Chirgadze, Nickolay Y.,Clawson, David K.,Hartley, Lawrence W.,Johnson, Lea M.,Jones, Noel D.,McKinney, Emma R.,Mihelich, Edward D.,Olkowski, Jennifer L.,Schevitz, Richard W.,Smith, Amy C.,Snyder, David W.,Sommers, Cynthia D.,Wery, Jean-Pierre
, p. 5159 - 5175 (2007/10/03)
The preceding papers of this series detail the development of functionalized indole-3-acetamides as inhibitors of hnps-PLA2. We describe here the extension of the structure-activity relationship to include a series of indole-3-glyoxamide derivatives. Functionalized indole-3-glyoxamides with an acidic substituent appended to the 4- or 5-position of the indole ring were prepared and tested as inhibitors of hnps-PLA2. It was found that the indole-3-glyoxamides with a 4-oxyacetic acid substituent had optimal inhibitory activity. These inhibitors exhibited an improvement in potency over the best of the indole-3-acetamides, and LY315920 (6m) was selected for evaluation clinically as an hnps-PLA2 inhibitor.
