- DERIVATIVES OF PHENYLMETHANONE AS FTO INHIBITORS
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Disclosed herein is a phenyl methanone derivative as an FTO inhibitor. Also disclosed herein is a pharmaceutical composition comprising the same, and a method for reducing food intake or appetite, inhibiting weight gain, promote weight loss, reducing bloo
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Paragraph 0069; 0070
(2019/07/17)
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- 6-SHOGAOL DERIVATIVES AND ACTIVITIES THEREOF
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Derivatives of 6-shogaol are described herein. Also described herein are methods of preparing the derivatives, as well as methods of using the derivatives to activate Nrf2 and to treat diseases associated with inflammation and/or oxidative stress.
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- Synthesis, evaluation, and metabolism of novel [6]-shogaol derivatives as potent Nrf2 activators
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Oxidative stress is a central component of many chronic diseases. The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2 p45-related factor 2 (Nrf2) system is a major regulatory pathway of cytoprotective genes against oxidative and electrophilic stress. Activation of the Nrf2 pathway plays crucial roles in the chemopreventive effects of various inducers. In this study, we developed a novel class of potent Nrf2 activators derived from ginger compound, [6]-shogaol (6S), using the Tg[glutathione S-transferase pi 1 (gstp1):green fluorescent protein (GFP)] transgenic zebrafish model. Investigation of structure-activity relationships of 6S derivatives indicates that the combination of an α,β-unsaturated carbonyl entity and a catechol moiety in one compound enhances the Tg(gstp1:GFP) fluorescence signal in zebrafish embryos. Chemical reaction and in vivo metabolism studies of the four most potent 6S derivatives showed that both α,β-unsaturated carbonyl entity and catechol moiety act as major active groups for conjugation with the sulfhydryl groups of the cysteine residues. In addition, we further demonstrated that 6S derivatives increased the expression of Nrf2 downstream target, heme oxygenase-1, in both a dose- and time-dependent manner. These results suggest that α,β-unsaturated carbonyl entity and catechol moiety of 6S derivatives may react with the cysteine residues of Keap1, disrupting the Keap1-Nrf2 complex, thereby liberating and activating Nrf2. Our findings of natural product-derived Nrf2 activators lead to design options of potent Nrf2 activators for further optimization.
- Zhu, Yingdong,Wang, Pei,Zhao, Yantao,Yang, Chun,Clark, Anderson,Leung, TinChung,Chen, Xiaoxin,Sang, Shengmin
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p. 243 - 254
(2016/04/20)
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- Therapeutic Aryl-Amido-Aryl Compounds and Their Use
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The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain aryl-amido-aryl compounds of the following formula (for convenience, collectively referred to herein as “AAA compounds”), which, inter alia, a
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Page/Page column 104
(2012/06/18)
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- THERAPEUTIC ARYL-AM I DO-ARYL COMPOUNDS AND THEIR USE
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The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain aryl-amido-aryl compounds of the following formula (for convenience, collectively referred to herein as "AAA compounds"), which, inter alia, a
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Page/Page column 171-172
(2011/04/14)
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- Synthesis of halogenated trimetoquinol derivatives and evaluation of their β-agonist and thromboxane A2 (TXA2) antagonist activities
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The 5,8-difluoro (4), 5-iodo (5), 8-iodo (6), and 5-trifluoromethyl (7) derivatives of trimetoquinol (TMQ, 1) have been synthesized and evaluated for their ability to stimulate β1 (guinea pig atria) and β2 (guinea pig trachea) adrenoceptors as well as for their inhibitory activity against U46619 [a thromboxane A2 (TXA2) mimetic]-mediated contraction of rat thoracic aorta and human platelet aggregation. Both 5 and 6 were considerably less active than TMQ on both β-adrenergic systems and gave a rank order of stimulatory potency of 1 >> 6 ≥ 5. Similarly, iodine substitution at either position also caused a reduction in TXA2 antagonist activity with a rank order potency of 1 > 6 >> 5. Compared to 1, however, 5-iodo-TMQ (5) showed a marked selectivity for blockade of U46619 responses in rat aorta over human platelets. On β-systems, 4 had reduced potency compared to TMQ and was similarly nonselective. Introduction of a trifluoromethyl group at the 5- position of TMQ completely abolished both β1- and β2-adrenergic agonist activities while imparting weak antagonist activity on β1 receptors. On TXA2 systems, both 4 and 7 possessed significantly decreased inhibitory activity compared to TMQ. The synthetic approaches to the synthesis of 8- (trifluoromethyl)-TMQ (8) are also described. The enantiomers of the 8-fluoro derivative (3) of TMQ were separated on a preparative Chiralcel OD column and evaluated on β-adrenergic systems and TXA2 systems. On β-adrenergic systems, (S)-(+)-8-fluoro-TMQ was at least 10-fold more potent than (R)-(-)- 8-fluoro-TMQ. Conversely, (R)-(-)-8-fluoro-TMQ was approximately 14-fold more potent as an antagonist of TXA2-mediated aggregation in human platelets than (S)-(+)-8-fluoro-TMQ. In contrast to platelets, (S)-(+)-8-fluoro-TMQ was an agonist in rat aorta whereas (R)-(-)-8-fluoro-TMQ was an antagonist.
- Markovich,Tantishaiyakul,Hamada,Miller,Romstedt,Shams,Shin,Fraundorfer,Doyle,Feller
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p. 466 - 479
(2007/10/02)
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- PHARMACOLOGICALLY ACTIVE COMPOUNDS, METHODS FOR THE PREPARATION THEREOF AND COMPOSITIONS CONTAINING THE SAME
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Pharmacologically active catechol derivatives of formula I I wherein R1 and R2 independently comprise hydrogen, alkyl, acyl, optionally substituted aroyl, lower alkylsulfonyl or alkylcabamoyl or taken together form a lower alkylidene or cycloalkylidene, X comprises an electronegative substituent such as halogen, nitro, cyano, lower alkylsulfonyl, sulfonamido, aldehyde, caboxyl or trifluoromethyl and R3 comprises hydrogen, halogen, hydroxy alkyl, amino, nitro, cyano, trifluoromethyl, lower alkylsulfonyl, sulfonamide, aldehyde, alkyl carbonyl, aralkylidene carbonyl or carboxyl or a group selected from wherein R4 comprises hydrogen, alkyl, cyano, carboxyl or acyl and R5 comprises hydrogen, cyano, carboxyl, alkoxycarbonyl, carboxyalkenyl, nitro, acyl, optionally substituted aroyl or heteroaroyl, hydroxyalkyl or carboxyalkyl or R4 and R5 together form a five to seven membered substituted cycloalkanone ring; -(CO)n(CH2)m-COR wherein n is 0-1 and m is 0-7 and R comprises hydroxy, alkyl, carboxyalkyl, optionally substituted alkene, alkoxy or optionally substituted amino; wherein R8 and R9 independently comprise hydrogen or one of the following optionally substituted groups; alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or together form an optionally substituted piperidyl group; -NH-CO-R10 wherein R10 comprises a substituted alkyl group
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- Synthesis of Some Novel Potent and Selective Catechol O-Methyltransferase Inhibitors
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A series of disubstituted catechol derivatives was synthesized and tested as potential COMT inhibitors.The most active compounds were more than 1000 times more potent (IC 50 = 3-6 nM) in vitro than the known COMT inhibitor, 3',4'-dihydroxy-2-methylpropiop
- Baeckstroem, Reijo,Honkanen, Erkki,Pippuri, Aino,Kairisalo, Pekka,Pystynen, Jarmo,et al.
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p. 841 - 846
(2007/10/02)
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