- Synthesis of Novel Nitrogen-Containing Heterocycle Bromophenols and Their Interaction with Keap1 Protein by Molecular Docking
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We previously reported 5,2’-dibromo-2,4’,5’-trihydroxydiphenylmethanoe (LM49), a bromophenol analogue that shows strong protection from oxidative stress injury owing to its superior anti-inflammatory, antioxidant, and anti-apoptotic properties. A series of novel nitrogen-containing heterocycle bromophenols were herein synthesized by introducing substituted piperidine, piperazine, and imidazole to modify 2-position of the lead compound LM49. By further evaluating their cytoprotective activity against H2O2 induced injury in EA.hy926 cells, 14 target bromophenols showed moderate-to-potent activity with EC50 values in the range of 0.9–6.3 μM, which were stronger than that of quercetin (EC50: 18.0 μM), a positive reference compound. Of these, the most potent compound 22b is a piperazine bromophenol with an EC50 value of 0.9 μM equivalent to the LM49. Molecular docking studies were subsequently performed to deduce the affinity and binding mode of derived halophenols toward the Keap1 Kelch domain, the docking results exhibited that the small molecule 22b is well accommodated by the bound region of Keap1-Kelch and Nrf2 through stable hydrogen bonds and hydrophobic interaction, which contributed to the enhancement of affinity and stability between the ligand and receptor. The above facts suggest that 22b is a promising pharmacological candidate for further cardiovascular drug development. Moreover, the targeting Keap1-Nrf2 protein-protein interaction may be an emerging strategy for halophenols to selectively and effectively activate Nrf2 triggering downstream protective genes defending against injury.
- Feng, Xiu E.,Wang, Qin Jin,Gao, Jie,Ban, Shu Rong,Li, Qing Shan
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Read Online
- Discovery of potent nucleotide pyrophosphatase/phosphodiesterase3 (NPP3) inhibitors with ancillary carbonic anhydrase inhibition for cancer (immuno)therapy
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Nucleotide pyrophosphatase/phosphodiesterase3 (NPP3) catalyzes the hydrolysis of extracellular nucleotides. It is expressed by immune cells and some carcinomas,e.g.of kidney and colon. Together with ecto-5′-nucleotidase (CD73), NPP3 produces immunosuppres
- Boshta, Nader M.,Bua, Silvia,Lee, Sang-Yong,Mirza, Salahuddin,Namasivayam, Vigneshwaran,Perotti, Arianna,Supuran, Claudiu T.,Müller, Christa E.
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p. 1187 - 1206
(2021/10/27)
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- PEST CONTROL METHOD
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PROBLEM TO BE SOLVED: To provide a method for controlling pests. SOLUTION: A compound represented by formula (I), or an N oxide thereof or salts thereof can control pests. [In formula (I), Q is a group represented by Q1 or the like (a bullet symbol is a binding site to a benzene ring), E is a C1-C6 chain hydrocarbon group or the like, R1 is a C1-C3 chain hydrocarbon group or the like, n is 0, 1, 2 or 3, where if n is 2 or 3, a plurality of R2 may be the same or different, R2 is a C1-C3 chain hydrocarbon group or the like]. SELECTED DRAWING: None COPYRIGHT: (C)2021,JPOandINPIT
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Paragraph 0394
(2021/10/02)
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- N-Heterocyclic Carbene Catalyzed Photoenolization/Diels–Alder Reaction of Acid Fluorides
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The combination of light activation and N-heterocyclic carbene (NHC) organocatalysis has enabled the use of acid fluorides as substrates in a UVA-light-mediated photochemical transformation previously observed only with aromatic aldehydes and ketones. Stoichiometric studies and TD-DFT calculations support a mechanism involving the photoactivation of an ortho-toluoyl azolium intermediate, which exhibits “ketone-like” photochemical reactivity under UVA irradiation. Using this photo-NHC catalysis approach, a novel photoenolization/Diels–Alder (PEDA) process was developed that leads to diverse isochroman-1-one derivatives.
- Agrawal, Arush,G?tze, Jan P.,Golz, Paul,Hopkinson, Matthew N.,Mavroskoufis, Andreas,Rajes, Keerthana,Ru?, Vincent
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supporting information
p. 3190 - 3194
(2020/01/24)
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- GLUCOPYRANOSYL DERIVATIVE AND USE THEREOF
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Provided are a glucopyranosyl derivative as a sodium-dependent glucose transporters inhibitor, especially as a SGLT1 inhibitor, a pharmaceutically acceptable salt or a stereoisomer thereof, a pharmaceutical composition thereof, and the uses of the compound and pharmaceutical composition thereof in the preparation of drugs for the treatment of diabetes and diabetes-related diseases.
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Paragraph 00227; 00353
(2019/08/12)
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- Glucopyranosyl derivative and its use in medicine (by machine translation)
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The invention relates to a as sodium-dependent glucose transporter (SGLTs) inhibitors of the glucopyranosyl derivative, containing the pharmaceutical composition and its use in medicine, in particular of formula (I) indicated by the glucopyranosyl derivative or its pharmaceutically acceptable salt or all of its stereoisomers, or containing the pharmaceutical composition and said derivative and pharmaceutical composition for the preparation of a medicine for treating diabetes and diabetes related diseases of the use. (by machine translation)
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Paragraph 0347-0350
(2018/07/28)
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- Discovery of LX2761, a sodium-dependent glucose cotransporter 1 (SGLT1) Inhibitor restricted to the intestinal lumen, for the treatment of diabetes
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The increasing number of people afflicted with diabetes throughout the world is a major health issue. Inhibitors of the sodiumdependent glucose cotransporters (SGLT) have appeared as viable therapeutics to control blood glucose levels in diabetic patents. Herein we report the discovery of LX2761, a locally acting SGLT1 inhibitor that is highly potent in vitro and delays intestinal glucose absorption in vivo to improve glycemic control.
- Goodwin, Nicole C.,Ding, Zhi-Ming,Harrison, Bryce A.,Strobel, Eric D.,Harris, Angela L.,Smith, Melinda,Thompson, Andrea Y.,Xiong, Wendy,Mseeh, Faika,Bruce, Debra J.,Diaz, Damaris,Gopinathan, Suma,Li, Ling,O'Neill, Emily,Thiel, Mary,Wilson, Alan G. E.,Carson, Kenneth G.,Powell, David R.,Rawlins, David B.
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p. 710 - 721
(2017/02/05)
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- C-ARYL GLUCOSIDE DERIVATIVE, PREPARATION METHODS THEREOF, AND MEDICAL APPLICATIONS THEREOF
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C-aryl glucoside derivatives, preparation methods thereof, and medical applications thereof are described. Specifically, compounds represented by formula I, and, tautomers, enantiomers, diastereomers, racemates, and pharmaceutically acceptable salts of th
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Paragraph 0233; 0234
(2016/08/29)
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- Iron-Catalyzed, Fluoroamide-Directed C-H Fluorination
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This communication describes a mild, amide-directed fluorination of benzylic, allylic, and unactivated C-H bonds mediated by iron. Upon exposure to a catalytic amount of iron(II) triflate (Fe(OTf)2), N-fluoro-2-methylbenzamides undergo chemoselective fluorine transfer to provide the corresponding fluorides in high yield. The reaction demonstrates broad substrate scope and functional group tolerance without the use of any noble metal additives. Mechanistic and computational experiments suggest that the reaction proceeds through short-lived radical intermediates with F-transfer mediated directly by iron.
- Groendyke, Brian J.,Abusalim, Deyaa I.,Cook, Silas P.
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supporting information
p. 12771 - 12774
(2016/10/13)
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- DIMETHYLBENZOIC ACID COMPOUNDS
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The present invention provides a compound of the Formula I: wherein A is: and W, Y, X, R1, R2, R3, and R4 are as defined herein, or a pharmaceutically acceptable salt thereof, for use as an inhibitor of the EP4 receptor.
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Page/Page column 12-13
(2015/07/07)
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- INHIBITORS OF SODIUM GLUCOSE COTRANSPORTER 1
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Inhibitors of sodium glucose cotransporter 1 (SGLT1), compositions comprising them, and methods of their use to treat diseases and disorders such as diabetes are disclosed. Particular compounds are of the formula (I): the various substituents of which are defined herein.
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Page/Page column 19
(2014/06/11)
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- Optimized S-trityl-l-cysteine-based inhibitors of kinesin spindle protein with potent in vivo antitumor activity in lung cancer xenograft models
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The mitotic kinesin Eg5 is critical for the assembly of the mitotic spindle and is a promising chemotherapy target. Previously, we identified S-trityl-l-cysteine as a selective inhibitor of Eg5 and developed triphenylbutanamine analogues with improved pot
- Good, James A. D.,Wang, Fang,Rath, Oliver,Kaan, Hung Yi Kristal,Talapatra, Sandeep K.,Podgórski, Dawid,MacKay, Simon P.,Kozielski, Frank
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p. 1878 - 1893
(2013/05/08)
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- C-Glucosides with heteroaryl thiophene as novel sodium-dependent glucose cotransporter 2 inhibitors
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Canagliflozin (1), a novel inhibitor for sodium-dependent glucose cotransporter 2 (SGLT2), has been developed for the treatment of type 2 diabetes. To investigate the effect of replacement of the phenyl ring in 1 with heteroaromatics, C-glucosides 2 were designed, synthesized, and evaluated for their inhibitory activities against SGLT2. Of these, 3-pyridyl, 2-pyrimidyl or 5-membered heteroaryl substituted derivatives showed highly potent inhibitory activity against SGLT2, while 5-pyrimidyl substitution was associated with slightly reduced activity. In particular, 2g (TA-3404) had remarkable anti-hyperglycemic effects in high-fat diet fed KK (HF-KK) mice.
- Koga, Yuichi,Sakamaki, Shigeki,Hongu, Mitsuya,Kawanishi, Eiji,Sakamoto, Toshiaki,Yamamoto, Yasuo,Kimata, Hirotaka,Nakayama, Keiko,Kuriyama, Chiaki,Matsushita, Yasuaki,Ueta, Kiichiro,Tsuda-Tsukimoto, Minoru,Nomura, Sumihiro
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p. 5561 - 5572
(2013/09/02)
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- HETERO-BICYCLIC DERIVATIVES AS HCV INHIBITORS
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Inhibitors of HCV replication of formula (I) including stereochemically isomeric forms, and salts, hydrates, solvates thereof, wherein R and R' have the meaning as defined herein. The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use, alone or in combination with other HCV inhibitors,in HCV therapy.
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Page/Page column 36
(2012/02/13)
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- CYCLOALKYL METHOXYBENZYL PHENYL PYRAN DERIVATIVES AS SODIUM DEPENDENT GLUCOSE CO TRANSPORTER (SGLT2) INHIBITORS
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The invention relates to the cycloalkyl methoxybenzyl phenyl pyran derivatives as Sodium dependent glucose co transporter (SGLT) inhibitors, particularly SGLT2 and method of treating diseases, conditions and/or disorders inhibited by SGLT2 with them, and processes for preparing them.
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Page/Page column 37-38
(2012/03/26)
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- FAMILY OF ARYL, HETEROARYL, O-ARYL AND O-HETEROARYL CARBASUGARS
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The present invention relates to a compound of the following formula (I): as well as its process of preparation, pharmaceutical and cosmetics composition comprising it and use thereof, notably as an inhibitor of the sodium-dependent glucose co-transporter, such as SGLTl, SGLT2 and SGLT3, in particular in the treatment or prevention of diabetes, and more particularly type-II diabetes, diabetes-related complications, such as arthritis of the lower extremities, cardiac infarction, renal insufficiency, neuropathy or blindness, hyperglycemia, hyperinsulinemia, obesity, hypertriglyceridemia, X syndrome and arteriosclerosis, as well as for its use as an anticancer, anti-infective, anti-viral, anti-thrombotic or anti- inflammatory drug, or for lightening, bleaching, depigmenting the skin, removing blemishes from the skin, particularly age spots and freckles, or preventing pigmentation of the skin.
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Page/Page column 71-72
(2012/12/13)
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- (1 S)-1,5-anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio- d -glucitol (TS-071) is a potent, selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for type 2 diabetes treatment
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Derivatives of a novel scaffold, C-phenyl 1-thio-d-glucitol, were prepared and evaluated for sodium-dependent glucose cotransporter (SGLT) 2 and SGLT1 inhibition activities. Optimization of substituents on the aromatic rings afforded five compounds with potent and selective SGLT2 inhibition activities. The compounds were evaluated for in vitro human metabolic stability, human serum protein binding (SPB), and Caco-2 permeability. Of them, (1S)-1,5-anhydro-1-[5- (4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-d-glucitol (3p) exhibited potent SGLT2 inhibition activity (IC50 = 2.26 nM), with 1650-fold selectivity over SGLT1. Compound 3p showed good metabolic stability toward cryo-preserved human hepatic clearance, lower SPB, and moderate Caco-2 permeability. Since 3p should have acceptable human pharmacokinetics (PK) properties, it could be a clinical candidate for treating type 2 diabetes. We observed that compound 3p exhibits a blood glucose lowering effect, excellent urinary glucose excretion properties, and promising PK profiles in animals. Phase II clinical trials of 3p (TS-071) are currently ongoing.
- Kakinuma, Hiroyuki,Oi, Takahiro,Hashimoto-Tsuchiya, Yuko,Arai, Masayuki,Kawakita, Yasunori,Fukasawa, Yoshiki,Iida, Izumi,Hagima, Naoko,Takeuchi, Hiroyuki,Chino, Yukihiro,Asami, Jun,Okumura-Kitajima, Lisa,Io, Fusayo,Yamamoto, Daisuke,Miyata, Noriyuki,Takahashi, Teisuke,Uchida, Saeko,Yamamoto, Koji
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experimental part
p. 3247 - 3261
(2010/10/02)
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- Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus (1)
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We discovered that C-glucosides 4 bearing a heteroaromatic ring formed metabolically more stable inhibitors for sodium-dependent glucose cotransporter 2 (SGLT2) than the O-glucoside, 2 (T-1095). A novel thiophene derivative 4b-3 (canagliflozin) was a highly potent and selective SGLT2 inhibitor and showed pronounced anti-hyperglycemic effects in high-fat diet fed KK (HF-KK) mice.
- Nomura, Sumihiro,Sakamaki, Shigeki,Hongu, Mitsuya,Kawanishi, Eiji,Koga, Yuichi,Sakamoto, Toshiaki,Yamamoto, Yasuo,Ueta, Kiichiro,Kimata, Hirotaka,Nakayama, Keiko,Tsuda-Tsukimoto, Minoru
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experimental part
p. 6355 - 6360
(2010/11/03)
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- PROCESS FOR THE PREPARATION OF COMPOUNDS USEFUL AS INHIBITORS OF SGLT
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The present invention is directed to a novel process for the preparation of compounds having inhibitory activity against sodium-dependent glucose transporter (SGLT) being present in the intestine or kidney.
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Page/Page column 76
(2009/04/25)
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- NOVEL BIAROMATIC COMPOUNDS, INHIBITORS OF THE P2X7-RECEPTOR
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The invention provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ar1 represents a group (II), (III), (IV) or (V), and A, Ar2, n, R1, R2, R3, R4 and R
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Page/Page column 68-69
(2008/06/13)
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- Methods of producing C-aryl glucoside SGLT2 inhibitors
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Method for the production of C-aryl glucoside SGLT2 inhibitors useful for the treatment of diabetes and related diseases. and intermediates thereof. The C-aryl glucosides may be complexed with amino acid complex forming reagents.
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