- N-(4-acetamidophenyl)-5-acetylfuran-2-carboxamide as a novel orally available diuretic that targets urea transporters with improved PD and PK properties
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Urea transporters (UTs) have been identified as new targets for diuretics. Functional deletion of UTs led to urea-selective urinary concentrating defects with relative salt sparing. In our previous study, a UT inhibitor with a diarylamide scaffold, which is denoted as 11a, was demonstrated as the first orally available UT inhibitor. However, the oral bioavailability of 11a was only 4.38%, which obstructed its clinical application. In this work, by replacing the nitro group of 11a with an acetyl group, 25a was obtained. Compared with 11a, 25a showed a 10 times stronger inhibitory effect on UT-B (0.14 μM vs. 1.41 μM in rats, and 0.48 μM vs. 5.82 μM in mice) and a much higher inhibition rate on UT-A1. Moreover, the metabolic stability both in vitro and in vivo and the drug-like properties (permeability and solubility) of 25a were obviously improved compared with those of 11a. Moreover, the bioavailability of 25a was 15.18%, which was 3 times higher than that of 11a, thereby resulting in significant enhancement of the diuretic activities in rats and mice. 25a showed excellent potential for development as a promising clinical diuretic candidate for targeting UTs to treat diseases that require long-term usage of diuretics, such as hyponatremia.
- Ge, Zemei,He, Jinzhao,Li, Min,Li, Runtao,Li, Xiaowei,Wang, Shuyuan,Xu, Yue,Yang, Baoxue,Zhang, Shun,Zhao, Yan,Zhou, Hong
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- Direct Alkoxycarbonylation of Heteroarenes via Cu-Mediated Trichloromethylation and in Situ Alcoholysis
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We report an efficient approach for direct alkoxycarbonylation of furans as well as other heteroarenes via a one-step copper-mediated reaction of three components (i.e., heteroarene, alcohol, and CHCl3). The copper additive was confirmed to simultaneously promote the reaction in three pathways: oxidant cracking, single electron transfer, and alcoholysis. By means of this protocol, various functionalized furancarboxylates and other heteroarenecarboxylates were facilely obtained in moderate to good yields.
- Jiang, Huanfeng,Jiang, Kai,Li, Yingwei,Luo, Wenkun,Yin, Biaolin
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supporting information
(2020/03/04)
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- FIVE-MEMBERED HETEROCYCLIC DERIVATIVE, METHOD FOR PRODUCING SAME, AND PHARMACEUTICAL COMPOSITION COMPRISING SAME
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The present invention relates to a five-membered heterocyclic compound having an analgesic effect and a pharmaceutical composition comprising a derivative of the five-membered heterocyclic compound. More specifically, the present invention relates to a me
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Paragraph 0062; 0063
(2019/04/29)
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- Room-Temperature Decarboxylative Couplings of α-Oxocarboxylates with Aryl Halides by Merging Photoredox with Palladium Catalysis
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Enabled by merging iridium photoredox catalysis and palladium catalysis, α-oxocarboxylate salts can be decarboxylatively coupled with aryl halides to generate aromatic ketones and amides at room temperature. DFT calculations suggest that this reaction proceeds through a Pd0-PdII-PdIII pathway, in which the PdIII intermediate is responsible for reoxidizing IrII to complete the IrIII-IrIII-IrII photoredox cycle. Like a mergin': Enabled by merging iridium photoredox catalysis and palladium catalysis, palladium-catalyzed decarboxylative coupling of α-oxocarboxylates with aryl halides can proceed at room temperature. DFT calculations suggest that a Pd0-PdII-PdIII catalytic cycle is merged with an IrIII-IrIII-IrII photoredox cycle, in which PdIII is responsible for oxidizing IrII to complete the photoredox cycle.
- Cheng, Wan-Min,Shang, Rui,Yu, Hai-Zhu,Fu, Yao
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supporting information
p. 13191 - 13195
(2015/09/15)
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- EP2 RECEPTOR AGONISTS
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A compound of formula (III): or a salt, solvate and chemically protected form thereof, wherein: R5 is an optionally substituted C5-20 aryl or C4-20alkyl group; L′ is a single bond, —O— or —C(═O)—; A is selected from the group consisting of: formulae (i) (ii) (iii) wherein X and Y are selected from the group consisting of: O and CR3; S and CR3; NH and CR3; NH and N; O and N; S and N; N and S; and N and O, and where the dotted lines indicate a double bond in the appropriate location, and where Q is either N or CH; D is selected from: formulae (i) (ii) (iii) (iv) (v) (vii) (viii) (ix) B is selected from the group consisting of: formulae (A) (B) where RP6 is selected from fluoro and chloro; and R2 is either: (i) —CO2H; (ii) —CONH2; (iii) —CH2—OH; or (iv) tetrazol-5-yl.
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Page/Page column 20
(2010/06/14)
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- Preferential inhibition of release of pro-inflammatory cytokines
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A method for preferentially inhibiting release of pro-inflammatory cytokines over release of anti-inflammatory cytokines using a fused pyrazolyl compound of formula (I): A is R or in which R is H, alkyl, aryl, cyclyl, heteroaryl, or heterocyclyl; each of
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Page/Page column 6
(2008/06/13)
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- Novel fused pyrazolyl compound
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A fused pyrazolyl compound of the following formula: wherein A, Ar1, Ar2, R1, R2, R3, and R4, are as defined herein. Also disclosed is a pharmaceutical composition containing an effective a
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Page/Page column 3; 5
(2010/02/14)
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- 1-Benzyl-3-(5′-hydroxymethyl-2′-furyl)-indazole (YC-1) derivatives as novel inhibitors against sodium nitroprusside-induced apoptosis
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Antiapoptotic agents based on 1-benzyl-3-(5′-hydroxymethyl-2′-furyl)indazole (22, YC-1) derivatives were explored for effective treatment of sepsis and septic shock. We found that compound 22, 1-benzyl-3-(5′-methoxymethyl-2′-furyl)indazole (27), and 1-phe
- Lien, Jin-Cherng,Lee, Fang-Yu,Huang, Li-Jiau,Pan, Shiow-Lin,Guh, Jih-Hwa,Teng, Che-Ming,Kuo, Sheng-Chu
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p. 4947 - 4949
(2007/10/03)
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- Method of treating disorders related to protease-activated receptors-induced cell activation
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A method of treating a disorder related to cell activation induced by protease-activated receptors. The method includes administering to a subject in need thereof a compound having a pyrazolyl core; an aryl group, via an via an alkylene linker, bonded to 1-N of the pyrazolyl core; a second aryl group fused at 4-C and 5-C of the pyrazolyl core; and a third aryl group bonded directly to 3-C of the pyrazolyl core.
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- Synthesis of 1-benzyl-3-(5′-hydroxymethyl-2′-furyl)indazole analogues as novel antiplatelet agents
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1-Benzyl-3-(5′-hydroxymethyl-2′-furyl)indazole (28, YC-1) was selected as the lead compound for systemic structural modification. After screening for antiplatelet activity, SARs of YC-1 analogues were established. Among these potent active derivatives, co
- Le,Lien,Huang,Huang,Tsai,Teng,Wu,Cheng,Kuo
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p. 3746 - 3749
(2007/10/03)
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- Benzoylation of deactivated compounds of the thiophene and furan series with phenyldichlorocarbenium tetrachloroaluminate
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The reactions of benzotrichloride with methyl and ethyl esters and nitriles of 2-thiophenecarboxylic and 2-furancarboxylic acids, with 2-acetylthiophene, 2-acetylfuran, and 2-thiophenaldehyde in the presence of an excess of anhydrous aluminum chloride hav
- Belen'kii,Gromova,Kolotaev,Krayushkin
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p. 256 - 263
(2007/10/03)
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- Palladium-Catalyzed Carbonylative Cross-Coupling Reaction of Arylboronic Acids with Aryl Electrophiles: Synthesis of Biaryl Ketones
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The carbonylative cross-coupling reaction of arylboronic acids with aryl electrophiles (ArI, ArBr, and ArOTf) to yield unsymmetrical biaryl ketones was carried out in anisole at 80°C in the presence of a palladium catalyst and a base. The reaction selectively proceeded under an atmospheric pressure of carbon monoxide when PdCl2(PPh3)2 (3 mol %)/K2CO3 (3 equiv) were used for aryl iodides and PdCl2(dppf) (3 mol %)/K2CO3 (3 equiv)/KI (3 equiv) for the bromides or the triflates. The carbonylation of arylboronic acids with benzyl halides gave aryl benzyl ketones.
- Ishiyama, Tatsuo,Kizaki, Hiroe,Hayashi, Takahiro,Suzuki, Akira,Miyaura, Norio
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p. 4726 - 4731
(2007/10/03)
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