- The discovery of novel small molecule allosteric activators of aldehyde dehydrogenase 2
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Aldehyde dehydrogenase 2 (ALDH2) plays important role in ethanol metabolism, and also serves as an important shield from the damage occurring under oxidative stress. A special inactive variant was found carried by 35–45% of East Asians. The variant carriers have recently been found at the higher risk for the diseases related to the damage occurring under oxidative stress, such as cardiovascular and cerebrovascular diseases. As a result, ALDH2 activators may potentially serve as a new class of therapeutics. Herein, N-benzylanilines were found as novel allosteric activators of ALDH2 by computational virtual screening using ligand-based and structure-based screening parallel screening strategy. Then a structural optimization was performed and has led to the discovery of the compound C6. It has good activity in vitro and in vivo, which could reduce infarct size by ~70% in ischemic stroke rat models. This study provided good lead compounds for the further development of ALDH2 activators.
- Tian, Wei,Guo, Jiapeng,Zhang, Qingsen,Fang, Shaoyu,Zhou, Ruolan,Hu, Jian,Wang, Mingping,Zhang, Yuefan,Guo, Jin-Min,Chen, Zhuo,Zhu, Ju,Zheng, Canhui
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Read Online
- ALDH2 agonist, preparation method and application thereof
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The invention belongs to the technical field of medicines, and particularly relates to an ALDH2 agonist, a preparation method and application thereof. The ALDH2 agonist has a novel structure and excellent ALDH2 agonist activity.
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Paragraph 0048-0053
(2019/07/10)
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- FUSED HETEROCYCLIC COMPOUND
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The present invention relates to a compound represented by the formula: wherein W is C(R 1 ) or N, each A is an optionally substituted aryl group or a heteroaryl group, X 1 is -NR 3 -Y 1 -, -O-, -S-, -SO-, -SO 2 or -CHR 3 - wherein R 3 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R 3 is optionally bonded to A to form an optionally substituted ring structure, R 1 is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, R 2 is a hydrogen atom or optionally substituted group bonded via a carbon atom or a sulfur atom, or R 1 and R 2 , or R 2 and R 3 are optionally bonded to form an optionally substituted ring structure, or a salt thereof, and a tyrosine kinase inhibitor or an agent for the prophylaxis or treatment of cancer, which contains this compound or a prodrug thereof.
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Page/Page column 94
(2008/06/13)
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- SUBSTITUTED ISOQUINOLINONES
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Isoquinolinone compounds are provided that are useful for the inhibition of ADP-platelet aggregation, particularly in the treatment of thrombosis and thrombosis related conditions or disorders.
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Page/Page column 56-57
(2010/02/11)
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- NITROGEN-CONTAINING HETEROCYCLIC COMPOUNDS AND BENAMIDE COMPOUNDS AND DRUGS CONTAINING THE SAME
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Disclosed are compounds represented by formula (I) which have triglyceride biosynthesis inhibitory activity in the liver and inhibitory activity against the secretion of apolipoprotein B-containing lipoprotein from the liver and particularly have excellent inhibitory activity against the secretion of apolipoprotein B-containing lipoprotein, are free from side effect of accumulation of lipids in the liver, and are useful for the treatment and prevention of hyperlipidemia and arteriosclerotic diseases. In formula (I), R1 and R2 represent alkyl, alkoxy, cycloalkyl, phenyl, alkenyl, alkynyl, or a five- or six-membered saturated or unsaturated heterocyclic ring, or R1 and R2, together with a nitrogen atom to which R1 and R2 are attached, may form a ring; R3 and R4 represent a hydrogen atom, alkyl, a halogen atom, hydroxyl, nitrile, alkoxycarbonyl, alkoxy, or carboxyl; or R2 and R3 may be attached to each other to form -(CH2)m-, -N=CH-, -CH=N-, or -(C1-6 alkyl)C=N-; A, D, E, and G each represent a carbon atom, or any one of A, D, E, and G represents a nitrogen atom with the other three each representing a carbon atom; Q represents a nitrogen atom or a carbon atom; Y represents a group represented by formula (II) wherein X represents a hydrogen atom, group -C(=O)N(R5)R6 or group -C(=O)OR7, R8 is absent or represents a bond, an oxygen atom, a sulfur atom, -SO2-, -SO-, -CH2-CH2-, or - CH=CH-, and R9 and R10 represent a hydrogen atom, alkyl, alkoxy, a halogen atom, or hydroxyl; and Z represents - (CH2)n-, -O-(CH2)i-, or -C(=O)NH-(CH2)i-.
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- Hydroxylamine derivative of 5-nitro-8-hydroxy quinoline
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Novel hydroxylamino derivatives of the formula wherein Ar is selected from the group consisting of mono- and polycyclic aromatics and hetero-aromatics, both optionally substituted with at least one member of the group consisting of --OH, halogen, --NO2, --CN, STR1 --R7, --OR8, STR2 --SO2 R12, --SO3 R13, --COOR14, aryl of 6 to 14 carbon atoms, --OR16, --CH2 --CN and --CH2 SO2 --R15, R1, R2, R3, R4, R5 and R6 are individually selected from the group consisting of hydrogen and alkyl of 1 to 8 carbon atoms, R7 and R8 are optionally unsaturated alkyl of 1 to 8 carbon atoms optionally substituted with at least one member of the group consisting of halogen and cyano, R9, R10, R11, R12 and R13 are alkyl of 1 to 8 carbon atoms, Z is selected from the group consisting of hydrogen, optionally unsaturated alkyl of 1 to 8 carbon atoms and acyl of an organic carboxylic acid of 2 to 18 carbon atoms, R14 is selected from the group consisting of hydrogen and alkyl of 1 to 8 carbon atoms, R15 is selected from the group consisting of alkyl of 1 to 8 carbon atoms and aryl of 6 to 14 carbon atoms optionally substituted with an alkyl of 1 to 8 carbon atoms, R16 is aryl of 6 to 14 carbon atoms optionally substituted with a member of the group consisting of alkyl of 1 to 8 carbon atoms, halogen and --NO2, the substituents of Ar being able to form rings containing at least one heteroatom selected from the group consisting of oxygen, nitrogen and sulfur and their non-toxic agriculturally acceptable acid addition salts with the proviso Ar is not phenyl nor phenyl with one methyl in the 2,3 or 4 position, a nitro in the 2- or 4-position, a chlorine in the 3- or 4-position, a bromine in the 4-position or a --CF3 in the 4-position nor 2,4-dinitrophenyl nor 2-nitro-4-trifluoromethylphenyl nor 2,6-dinitrophenyl nor 2,4,6-trinitrophenyl nor 2,4-dinitro-6-trifluoromethylphenyl useful for increasing vegetation growth and increasing crop yields and their preparation.
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