160664-95-9Relevant articles and documents
S29434, a quinone reductase 2 inhibitor: Main biochemical and cellular characterization
Boutin, Jean A.,Bouillaud, Frederic,Janda, Elzbieta,Gacsalyi, István,Guillaumet, Gérald,Hirsch, Etienne C.,Kane, Daniel A.,Nepveu, Fran?oise,Reybier, Karine,Dupuis, Philippe,Bertrand, Marc,Chhour, Monivan,Le Diguarher, Thierry,Antoine, Mathias,Brebner, Karen,Da Costa, Hervé,Ducrot, Pierre,Giganti, Adeline,Goswami, Vishalgiri,Guedouari, Hala,Michel, Patrick P.,Patel, Aakash,Paysant, Jér?me,Stojko, Johann,Viaud-Massuard, Marie-Claude,Ferry, Gilles
supporting information, p. 269 - 285 (2019/05/14)
Quinone reductase 2 (QR2, E.C. 1.10.5.1) is an enzyme with a feature that has attracted attention for several decades: in standard conditions, instead of recognizing NAD(P)H as an electron donor, it recognizes putative metabolites of NADH, such as N-methyl- and N-ribosyl-dihydronicotinamide. QR2 has been particularly associated with reactive oxygen species and memory, strongly suggesting a link among QR2 (as a possible key element in pro-oxidation), autophagy, and neurodegeneration. In molecular and cellular pharmacology, understanding physiopathological associations can be difficult because of a lack of specific and powerful tools. Here, we present a thorough description of the potent, nanomolar inhibitor [2-(2-methoxy-5H-1,4b,9-triaza(indeno[2,1-a]inden-10-yl)ethyl]-2-furamide (S29434 or NMDPEF; IC505 5–16 nM) of QR2 at different organizational levels. We provide full detailed syntheses, describe its cocrystallization with and behavior at QR2 on a millisecond timeline, show that it penetrates cell membranes and inhibits QR2-mediated reactive oxygen species (ROS) production within the 100 nM range, and describe its actions in several in vivo models and lack of actions in various ROS-producing systems. The inhibitor is fairly stable in vivo, penetrates cells, specifically inhibits QR2, and shows activities that suggest a key role for this enzyme in different pathologic conditions, including neurodegenerative diseases.
Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the γ-Aminobutyric Acid Type A Receptor (GABAAR) α6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability
Knutson, Daniel E.,Kodali, Revathi,Divovi?, Branka,Treven, Marco,Stephen, Michael R.,Zahn, Nicolas M.,Dobri?i?, Vladimir,Huber, Alec T.,Meirelles, Matheus A.,Verma, Ranjit S.,Wimmer, Laurin,Witzigmann, Christopher,Arnold, Leggy A.,Chiou, Lih-Chu,Ernst, Margot,Mihovilovic, Marko D.,Savi?, Miroslav M.,Sieghart, Werner,Cook, James M.
, p. 2422 - 2446 (2018/03/26)
Recent reports indicate that α6β2/3γ2 GABAAR selective ligands may be important for the treatment of trigeminal activation-related pain and neuropsychiatric disorders with sensori-motor gating deficits. Based on 3 functionally α6β2/3γ2 GABAAR selective pyrazoloquinolinones, 42 novel analogs were synthesized, and their in vitro metabolic stability and cytotoxicity as well as their in vivo pharmacokinetics, basic behavioral pharmacology, and effects on locomotion were investigated. Incorporation of deuterium into the methoxy substituents of the ligands increased their duration of action via improved metabolic stability and bioavailability, while their selectivity for the GABAAR α6 subtype was retained. 8b was identified as the lead compound with a substantially improved pharmacokinetic profile. The ligands allosterically modulated diazepam insensitive α6β2/3γ2 GABAARs and were functionally silent at diazepam sensitive α1β2/3γ2 GABAARs, thus no sedation was detected. In addition, these analogs were not cytotoxic, which render them interesting candidates for treatment of CNS disorders mediated by GABAAR α6β2/3γ2 subtypes.
HEPATITIS C INHIBITOR COMPOUNDS
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Page/Page column 40, (2013/03/26)
A compound of formula (I) useful for the treatment or prevention of hepatitis C viral infection, (Formula (I)) wherein: X1 and X2 are each independently CRB or N; RB is H, (C1-6)alkyl, (C1-6/sub
