23915-78-8Relevant articles and documents
SUBSTITUTED CYCLOLAKYLS AS MODULATORS OF THE INTEGRATED STRESS PATHWAY
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Page/Page column 255; 278, (2020/11/12)
Provided herein are compounds, compositions, and methods useful for modulating the integrated stress response (ISR) and for treating related diseases, disorders and conditions.
Neurogenic and neuroprotective donepezil-flavonoid hybrids with sigma-1 affinity and inhibition of key enzymes in Alzheimer's disease
Estrada Valencia, Martín,Herrera-Arozamena, Clara,de Andrés, Lucía,Pérez, Concepción,Morales-García, José A.,Pérez-Castillo, Ana,Ramos, Eva,Romero, Alejandro,Vi?a, Dolores,Yá?ez, Matilde,Laurini, Erik,Pricl, Sabrina,Rodríguez-Franco, María Isabel
, p. 534 - 553 (2018/07/25)
In this work we describe neurogenic and neuroprotective donepezil-flavonoid hybrids (DFHs), exhibiting nanomolar affinities for the sigma-1 receptor (σ1R) and inhibition of key enzymes in Alzheimer's disease (AD), such as acetylcholinesterase (AChE), 5-lipoxygenase (5-LOX), and monoamine oxidases (MAOs). In general, new compounds scavenge free radical species, are predicted to be brain-permeable, and protect neuronal cells against mitochondrial oxidative stress. N-(2-(1-Benzylpiperidin-4-yl)ethyl)-6,7-dimethoxy-4-oxo-4H-chromene-2-carboxamide (18) is highlighted due to its interesting biological profile in σ1R, AChE, 5-LOX, MAO-A and MAO-B. In phenotypic assays, it protects a neuronal cell line against mitochondrial oxidative stress and promotes maturation of neural stem cells into a neuronal phenotype, which could contribute to the reparation of neuronal tissues. Molecular modelling studies of 18 in AChE, 5-LOX and σ1R revealed the main interactions with these proteins, which will be further exploited in the optimization of new, more efficient DFHs.
Optimization of chromone-2-carboxamide melanin concentrating hormone receptor 1 antagonists: Assessment of potency, efficacy, and cardiovascular safety
Lynch, John K.,Freeman, Jennifer C.,Judd, Andrew S.,Iyengar, Rajesh,Mulhern, Mathew,Zhao, Gang,Napier, James J.,Wodka, Dariusz,Brodjian, Sevan,Dayton, Brian D.,Falls, Doug,Ogiela, Christopher,Reilly, Regina M.,Campbell, Thomas J.,Polakowski, James S.,Hernandez, Lisa,Marsh, Kennan C.,Shapiro, Robin,Knourek-Segel, Victoria,Droz, Brian,Bush, Eugene,Brune, Michael,Preusser, Lee C.,Fryer, Ryan M.,Reinhart, Glenn A.,Houseman, Kathryn,Diaz, Gilbert,Mikhail, Ann,Limberis, James T.,Sham, Hing L.,Collins, Christine A.,Kym, Philip R.
, p. 6569 - 6584 (2007/10/03)
Evaluation of multiple structurally distinct series of melanin concentrating hormone receptor 1 antagonists in an anesthetized rat cardiovascualar assay led to the identification of a chromone-2-carboxamide series as having excellent safety against the chosen cardiovascular endpoints at high drug concentrations in the plasma and brain. Optimization of this series led to considerable improvements in affinity, functional potency, and pharmacokinetic profile. This led to the identification of a 7-fluorochromone-2-carboxamide (22) that was orally efficacious in a diet-induced obese mouse model, retained a favorable cardiovascular profile in rat, and demonstrated dramatic improvement in effects on mean arterial pressure in our dog cardiovascular model compared to other series reported by our group. However, this analogue also led to prolongation of the QT interval in the dog that was linked to affinity for hERG channel and unexpectedly potent functional blockade of this ion channel.