- S29434, a quinone reductase 2 inhibitor: Main biochemical and cellular characterization
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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.
- 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
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supporting information
p. 269 - 285
(2019/05/14)
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- PYRAZOLE DERIVATIVES AS MALT1 INHIBITORS
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Disclosed are compounds, compositions and methods for treating of diseases, syndromes, conditions, and disorders that are affected by the modulation of MALT 1. Such compounds are represented by Formula (I) as follows: wherein R1, R2, R3, R4, R5, and G, are defined herein.
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Paragraph 0579-0581
(2020/01/04)
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- 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
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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.
- 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.
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p. 2422 - 2446
(2018/03/26)
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- LIGANDS SELECTIVE TO ALPHA 6 SUBUNIT-CONTAINING GABAA RECEPTORS ANS THEIR METHODS OF USE
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Provided herein are novel pyrazoloquinolinone compounds and method of using such compounds to treat disorders such as neuropsychiatric disorders with sensorimotor gating deficits, such as schizophrenia, tic disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, panic disorder, Huntington's disease and nocturnal enuresis;depression; temporomandibular myofascial pain; disorders of trigeminal nerve, such as trigeminal neuralgia and trigeminal neuropathy; migraine; and tinnitus.
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Paragraph 00160
(2016/12/22)
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- NEW POSITIVE ALLOSTERIC MODULATORS OF NICOTINIC ACETYLCHOLINE RECEPTOR
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The present invention relates to compounds useful in therapy, to compositions comprising said compounds, and to methods of treating diseases comprising administration of said compounds. The compounds referred to are positive allosteric modulators (PAMs) of the nicotinic acetylcholine alpha7 receptor.
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Page/Page column 14
(2013/02/28)
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- HEPATITIS C INHIBITOR COMPOUNDS
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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
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Page/Page column 40
(2013/03/26)
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- TETRAZOLE COMPOUNDS AS OREXIN RECEPTOR ANTAGONISTS
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The invention relates to tetrazole compounds of formula (I) wherein X, Y, Z, R1, R2 and R3 are as described in the description; to pharmaceutically acceptable salts thereof, and to the use of such compounds use as medicaments, especially as orexin receptor antagonists.
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Page/Page column 34
(2011/04/25)
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- TETRAZOLE COMPOUNDS AS OREXIN RECEPTOR ANTAGONISTS
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The invention relates to tetrazole compounds of formula (I) wherein X, Y, Z, R1, R2 and R3 are as described in the description; to pharmaceutically acceptable salts thereof, and to the use of such compounds use as medicaments, especially as orexin receptor antagonists.
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Page/Page column 81
(2010/01/07)
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- Synthesis of 4- and 6-azaindoles via the fischer reaction
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Contrary to the common idea that Fischer indole cyclization often cannot be effectively applied to the synthesis of the corresponding azaindoles, we show that this approach can be actually very efficient for the formation of 4- and 6-azaindoles bearing an electron-donating group on the starting pyridylhydrazines. Two 4-azaindole natural product analogues were synthesized in a few steps and very good overall yields.
- Jeanty, Matthieu,Blu, Jerome,Suzenet, Franck,Guillaumet, Gerald
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supporting information; experimental part
p. 5142 - 5145
(2009/12/28)
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- PYRAZOLE DERIVATIVE
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A compound represented by Formula (I): wherein Ar1 represents Formula (II): Ar2 represents a 5- or 6-membered aromatic heterocyclic group which may be substituted; and X represents Formula (III): a salt thereof, or a solvate of the compound or the salt. A potent platelet aggregation suppressant which does not inhibit COX-1 and COX-2 is provided.
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Page/Page column 24-25
(2010/11/27)
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- AMIDOPYRAZOLE DERIVATIVE
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A platelet coagulation inhibitor which inhibits neither COX-1 nor COX-2 is provided. The inhibitor is a compound represented by general formula (I): wherein Ar1 and Ar2 independently represent a 5- or 6-membered aromatic heterocyclic group optionally substituted with 1 to 3 substituents, or a phenyl group optionally substituted with 1 to 3 substituents; R1 represents a lower acyl group, carboxyl group, a lower alkoxycarbonyl group, a lower alkoxy group, a lower alkyl group optionally substituted with 1 or 2 substituents, a carbamoyl group optionally substituted with 1 or 2 substituents, an oxamoyl group optionally substituted with 1 or 2 substituents, an amino group optionally substituted with 1 or 2 substituents, a 4- to 7-membered alicyclic heterocyclic group optionally substituted with 1 or 2 substituents, a phenyl group optionally substituted with 1 to 3 substituents, or a 5- or 6-membered aromatic heterocyclic group optionally substituted with 1 to 3 substituents; and R2 represents hydrogen atom, a halogeno group, or the like.
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Page/Page column 20
(2010/11/23)
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- Pyridazino quinoline compounds
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The invention relates to pyridazinoquinoline compounds of the formulas B and B′ wherein Ring A is selected from an ortho fused aromatic or heteroaromatic five- or six-membered ring and R1, R3and R4are substituents selected from halo, OH, OCF3, NO2, CN, NR′R″, SO2NR′R″, SOmR′alkyl, and a variety of alkyl, aryl, heterocyclic and heteroaryl groups, to pharmaceutical compositions containing them and to methods utilizing them for the treatment of neurological disorders.
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- Pyridazion quinoline compounds
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The present invention relates to compounds, pharmaceutical compositions and methods of using compounds of formula (I) in the treatment and/or prevention of certain diseases or conditions. In formula (I), A is chosen from ortho substituted aryl or heteroaryl species, X is chosen from --OH, --SH, NHR and R 1 or R 2 is chosen from --(CH 2) n L wherein L may be selected from a variety of substituents including aryl, heteroaryl and heterocyclic groups. The compounds are useful in treating and/or preventing neurological disorders associated with excitatory amino acids. STR1
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- Certain cycloalkyl and azacycloalkyl pyrrolopyridines; a new class of gaba rain receptor ligands
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The present invention encompasses compounds of the formula: STR1 and pharmaceutically acceptable non-toxic salts thereof wherein: A represents nitrogen or C--H, andB represents nitrogen or C--H, with the proviso that when A is nitrogen, B is C--H, and whe
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