- Discovery of Novel Bicyclic Imidazolopyridine-Containing Human Urate Transporter 1 Inhibitors as Hypouricemic Drug Candidates with Improved Efficacy and Favorable Druggability
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Lesinurad is a uricosuric agent for the treatment of hyperuricemia associated with gout, which was found lacking in efficacy and safety. Here, scaffold hopping and molecular hybridization were exploited to modify all the structural components of lesinurad, and 36 novel compounds bearing bicyclic imidazolopyridine core were obtained. In a mouse model of acute hyperuricemia, 29 compounds demonstrated increased serum uric acid (SUA)-reducing activity; SUA was treated with 12, 23, and 29 about fourfold lower compared with that of lesinurad. Moreover, 23 exhibited stronger URAT1 inhibition activity (IC50 = 1.36 μM) than lesinurad (IC50 = 5.54 μM). Additionally, 23 showed favorable safety profiles, and no obvious acute toxicity was observed in Kunming mice under a single dose of 1000 mg·kg-1. 23 also achieved excellent pharmacokinetic properties with the oral bioavailability of 59.3%. Overall, all the results indicated that 23 is a promising drug candidate in the treatment of hyperuricemia and gout.
- Zhao, Tong,Zhang, Jian,Tao, Yucen,Liao, Hui,Zhao, Fabao,Liang, Ruipeng,Shi, Xiaoyu,Zhang, Zhijiao,Ji, Jianbo,Wu, Ting,Pang, Jianxin,Liu, Xinyong,Zhan, Peng
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p. 4218 - 4237
(2022/02/10)
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- A new 2D Cu-MOF constructed from carboxylate ligands containing C-H?π interactions as a recyclable responsive luminescent sensor for VOCs
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A new type of 2D metal-organic framework (MOF), namely Cu-MOF, was constructed from Cu(NO3)2·3H2O and the novel ligand 1,4-bis(4-naphthoic acid)benzene. The C-H?π interactions in the Cu-MOF effectively reduced aggregation-caused quenching (ACQ) due to restrictions in intramolecular motion (RIM), increased fluorescence, and controlled crystal packing properties, resulting in low dimensional parallelogram channels and a responsive “turn-on” fluorescence. The activated Cu-MOF exhibited excellent chemical sensing properties to various volatile organic compounds (VOCs) and showed excellent recyclability.
- Liu, Chengxin,Cui, Jin,Wang, Yufang,Zhang, Mingjie
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supporting information
p. 4124 - 4128
(2021/04/06)
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- CRYSTAL FORM OF URATE TRANSPORTER 1 INHIBITOR AND PREPARATION METHOD AND USE THEREOF
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The present invention provides a crystal form of urate transporter 1 inhibitor and a preparation method and use thereof. The crystal form is characterized by a stable state of appearance and a capability of further improving the purity and storage stability of the compound, etc., and suitable as a pharmaceutical raw material.
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- COMPOUNDS FOR INHIBITION OF ALPHA 4β7 INTEGRIN
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The present disclosure provides a compound of Formula (I); or a pharmaceutically acceptable salt thereof as described herein. The present disclosure also provides pharmaceutical compositions comprising a compound of Formula (I), processes for preparing compounds of Formula (I), and therapeutic methods for treating inflammatory disease.
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Paragraph 0392; 0393
(2020/05/29)
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- METHOD FOR PREPARING URATE TRANSPORTER 1 INHIBITOR
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Provided is a method for preparing a URAT1 inhibitor, 2-((5-bromo-4-((4-bromonaphthalen-1-yl)methyl)-4H-1,2,4-triazol-3-yl)thio) acetic acid represented by the following formula ZXS-BR, the reaction equation of which being shown as follows. Compared with the prior art, the preparation method provided by the present application is of low cost, ease of handling, ease of quality control, and applicable to industrialization.
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- Carbocation Catalyzed Bromination of Alkyl Arenes, a Chemoselective sp3 vs. sp2 C?H functionalization.
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The versatility of the trityl cation (TrBF4) as a highly efficient Lewis acid organocatalyst is demonstrated in a light induced benzylic brominaion of alkyl-arenes under mild conditions. The reaction was conducted at ambient temperature under common hood light (55 W fluorescent light) with catalyst loadings down to 2.0 mol% using N-bromosuccinimide (NBS) as the brominating agent. The protocol is applicable to an extensive number of substrates to give benzyl bromides in good to excellent yields. In contrast to most previously reported strategies, this protocol does not require any radical initiator or extensive heating. For electron-rich alkyl-arenes, the trityl ion catalyzed bromination could be easily switched between benzylic sp3 C?H functionalization and arene sp2 C?H functionalization by simply alternating the solvent. This chemoselective switch allows for high substrate control and easy preparation of benzyl bromides and bromoarenes, respectively. The chemoselective switch was also applied in a one-pot reaction of 1-methylnaphthalene for direct introduction of both sp3 C?Br and sp2 C?Br functionality. (Figure presented.).
- Ni, Shengjun,El Remaily, Mahmoud Abd El Aleem Ali Ali,Franzén, Johan
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supporting information
p. 4197 - 4204
(2018/09/25)
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- Synthesis method of 4-bromonaphthalene-1-carbonitrile
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The invention discloses a synthesis method of 4-bromonaphthalene-1-carbonitrile. The method comprises the following steps: 1, replacing hydrogen on 1-methyl naphthalene benzene ring with bromine by taking 1-methyl naphthalene as a raw material, so as to obtain 4-bromine-1-methyl naphthalene (I); 2, replacing hydrogen on the methyl of the 4-bromine-1-methyl naphthalene (I) with bromine to obtain 4-bromine-1-bromine methyl naphthalene (II); 3, carrying out a sommelet reaction on the 4-bromine-1-bromine methyl naphthalene (II) to obtain 4-bromine-1-naphthaldehyde (III); 4, oximating the 4-bromine-1-naphthaldehyde (III) to obtain 4-bromine-1-naphthaldehyde oxime (IV); 5, carrying out dehydration on the 4-bromine-1-naphthaldehyde oxime (IV) to obtain the 4-bromonaphthalene-1-carbonitrile (V). The synthesis method has the advantages of being reasonable in process route design, cheap and available in raw and auxiliary materials, high in yield, low in cost, suitable for industrial production, and the like.
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- COMPOUNDS FOR BINDING PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9)
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The present disclosure relates to novel compounds, methods, and compositions capable of binding to PCSK9, thereby modulating PCSK9 proprotein convertase enzyme activity. The compounds of the disclosure include compounds Formula (I).
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Paragraph 0377
(2017/09/15)
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- A process for the preparation of halogenated aryl armor cyanogen (by machine translation)
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The present invention provides a method for the preparation of halogenated aryl armor cyanogen, comprising the following steps, the structure of the compound of the formula IV, iodine in water after the reaction the solvent, the structure of formula I is the halogenated aryl armor cyanogen. Green of the present invention the process for the preparation of halogenated aryl armor cyanogen, the compound of the formula IV, the ammonia in the iodine directly after the reaction in a solvent, to obtain halogenated aryl armor cyanogen (halogenated aryl a cyanogen derivatives). The invention provides a simple process reaction route, mild condition, does not use the hypertoxic cuprous cyanide, relatively high purity and yield, and does not need to, microwave and measures to improve the yield, in terms of industrial production more practical; in addition, the present invention provides method for the preparation of, its corresponding post-treatment step is simple, is more suitable for large scale industrial production. (by machine translation)
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- Discovery of a flexible triazolylbutanoic acid as a highly potent uric acid transporter 1 (URAT1) inhibitor
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In order to systematically explore and understand the structure-activity relationship (SAR) of a lesinurad-based hit (1c) derived from the replacement of the S atom in lesinurad with CH2, 18 compounds (1a-1r) were designed, synthesized and subjected to in vitro URAT1 inhibitory assay. The SAR exploration led to the discovery of a highly potent flexible URAT1 inhibitor, 1q, which was 31-fold more potent than parent lesinurad (IC50 = 0.23 μM against human URAT1 for 1q vs. 7.18 μM for lesinurad). The present study discovered a flexible molecular scaffold, as represented by 1q, which might serve as a promising prototype scaffold for further development of potent URAT1 inhibitors, and also demonstrated that the S atom in lesinurad was not indispensable for its URAT1 inhibitory activity.
- Tian, He,Liu, Wei,Zhou, Zhixing,Shang, Qian,Liu, Yuqiang,Xie, Yafei,Liu, Changying,Xu, Weiren,Tang, Lida,Wang, Jianwu,Zhao, Guilong
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- UiO-67-type Metal-Organic Frameworks with Enhanced Water Stability and Methane Adsorption Capacity
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The structure and properties of two new UiO-67-type metal-organic frameworks, along with their linker synthesis and powder and single crystal synthesis, are presented. The new MOFs, UiO-67-Me and UiO-67-BN, are based on 3,3′-dimethylbiphenyl and 1,1′-binaphthyl linker scaffolds, and show a much higher stability to water than the thoroughly investigated UiO-67, which is based on the biphenyl scaffold. On the basis of structure models obtained from single crystal X-ray diffraction, it is seen that these linkers are partly shielding the Zr cluster. The new materials have higher density than UiO-67, but show a higher volumetric adsorption capacity for methane. UiO-67-BN exhibits excellent reversible water sorption properties, and enhanced stability to aqueous solutions over a wide pH range; it is to the best of our knowledge the most stable Zr-MOF that is isostructural to UiO-67 in aqueous solutions.
- ?ien-?Degaard, Sigurd,Bouchevreau, Boris,Hylland, Knut,Wu, Lianpao,Blom, Richard,Grande, Carlos,Olsbye, Unni,Tilset, Mats,Lillerud, Karl P.
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supporting information
p. 1986 - 1991
(2016/03/19)
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- Exploiting the co-reliance of tumours upon transport of amino acids and lactate: Gln and Tyr conjugates of MCT1 inhibitors
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Glutamine and tyrosine-based amino acid conjugates of monocarboxylate transporter types 1 and 2 inhibitors (MCT1/2) were designed, synthesized and evaluated for their potency in blocking the proliferation of a human B lymphoma cell line that expresses the transporters Asct2, LAT1 and MCT1. Appropriate placement of an amino acid transporter recognition element was shown to augment anti-tumour efficacy vs. Raji cells. Amino acid conjugation also improves the pharmacodynamic properties of experimental MCT1/2 inhibitors.
- Nair, Reji N.,Mishra, Jitendra K.,Li, Fangzheng,Tortosa, Mariola,Yang, Chunying,Doherty, Joanne R.,Cameron, Michael,Cleveland, John L.,Roush, William R.,Bannister, Thomas D.
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p. 900 - 905
(2016/06/08)
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- A quinoidal bis-phenalenyl-fused porphyrin with supramolecular organization and broad near-infrared absorption
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A bis-phenalenyl-fused porphyrin has been synthesized by thermal dehydro-aromatization reaction regioselectively as a single syn-isomer. X-ray crystal structure revealed that both phenalenyl units of this porphyrin have close π-π contacts forming continuous network of interacting porphyrin rings. A broad and intense NIR absorption can be attributed to quinoidal character of bis-phenalenyl-fused porphyrin.
- Diev, Vyacheslav V.,Femia, Denise,Zhong, Qiwen,Djurovich, Peter I.,Haiges, Ralf,Thompson, Mark E.
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supporting information
p. 1949 - 1952
(2016/02/12)
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- Novel D-π3-(A)1-3 multibranched chromophores as an efficient two-photon-induced polymerization initiator
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The ability of novel branched chromophores that contained a triphenylamine group as donor, naphthalene as π-bridge and pyridyl as acceptor group, to act as two-photon absorption and two-photon induced polymerization initiators were investigated. Linear and nonlinear optical spectra revealed that chromophores with large dipolar moment change gave strong intramolecular charge-transfer characteristics that exhibited enhanced two-photon absorption cross-section. A variety of micro-objects were fabricated, using an acrylate matrix, that contained the novel chromophores as two-photon induced polymerization initiator. Molecular energy levels, electrochemistry and linear absorption spectra, as well as one-photon fluorescence quenching measurements supported the hypothesis that two-photon induced polymerization proceeds via intermolecular charge-transfer from initiator to monomer and, that the chromophore firstly generates the exciton via two-photon absorption and then transfers charge to the acrylate monomer which then polymerises.
- Wang, Xiaomei,Jin, Feng,Zhang, Weizhou,Tao, Xutang,Duan, Xuan-Ming,Jiang, Minhua
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scheme or table
p. 57 - 64
(2010/12/24)
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- ISOXAZOLINES DERIVATIVES AND THEIR USE AS PESTICIDE
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The invention relates to new pyrimidine compounds of formula (I) wherein the variables have the meaning as indicated in the claims; in free form and in salt form; and optionally the enantiomers and geometrical isomers thereof. The compounds of formula (I) are useful in the control of parasites, in particular ectoparasites, in and on warmblooded animals.
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Page/Page column 34
(2010/08/04)
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- Photochromism of a radical diffusion-inhibited hexaarylbiimidazole derivative with intense coloration and fast decoloration performance
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(Figure Presented) We report the synthesis and the photochromic behavior of a newly designed, photochromic, radical diffusion-inhibited hexaarylbiimidazole (HABI) derivative with markedly improved photochromic performance in coloration and decoloration rates as well as greater optical density in the colored state. The thermal bleaching rate (τ1/2 = 260 ms at 295 K) is the fastest among the reported ones for HABI derivatives.
- Fujita, Kana,Hatano, Sayaka,Kato, Daisuke,Abe, Jiro
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supporting information; experimental part
p. 3105 - 3108
(2009/05/07)
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- An efficient and enantioselective synthesis of suitably protected β-[1-(4-malonyl)naphthyl]-L-alanine and β-[1-(4-malonylmethyl) naphthyl]-L-alanine: Novel fluorescent and non-hydrolysable phosphotyrosine mimetics
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Molecular dynamics simulations based on the structure of the Grb7 SH2 domain in complex with the ErbB2 phosphorylated peptide pTyr1139 have suggested that β-[1-(4-malonyl)naphthyl]-L-alanine (L-mNal) may be accommodated in the pTyr binding pocket and offer additional beneficial interactions. Therefore, this compound and its analog β-[1-(4-malonylmethyl)naphthyl]-L-alanine (L-mmNal), which are new non-hydrolysable phosphotyrosine mimetics, have been prepared by the catalytic asymmetric hydrogenation of the corresponding prochiral enamides with excellent enantioselectivities. These compounds and their dehydro derivatives show interesting fluorescent properties. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.
- Chen, Huixiong,Luzy, Jean-Philippe,Gresh, Nohad,Garbay, Christiane
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p. 2329 - 2335
(2007/10/03)
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- High thermal stability of 5′-5′-linked alternate Hoogsteen triplexes at physiological pH
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(Chemical Equation Presented) DNA glue: A new alternate-strand linker (shown in green) has been synthesized that can connect two short DNA sequences (5- and 9-mers, yellow) and bind to double-stranded DNA through major-groove interactions at pH 7.2 (see m
- Filichev, Vyacheslav V.,Nielsen, Mads C.,Bomholt, Niels,Jessen, Carsten H.,Pedersen, Erik B.
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p. 5311 - 5315
(2007/10/03)
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- AMINOETHANOL DERIVATIVES
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The present invention provides a pharmaceutical agent having cholesteryl ester transfer protein inhibitory action and useful as a blood lipid lowering agent and the like. The present invention relates to a compound represented by the formula wherein Ar1 is an aromatic ring group optionally having substituents, Ar2 is an aromatic ring group having substituents, OR'' is an optionally protected hydroxyl group, R is an acyl group, R' is a hydrogen atom or a hydrocarbon group optionally having substituents, or a salt thereof, and a pharmaceutical composition containing a compound of the formula (I) or a salt thereof or a prodrug thereof.
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Page/Page column 55
(2010/11/30)
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- Silicon-based aromatic transferring linkers for traceless solid-phase synthesis of aryl-, polyaryl-, and heteroaryl-containing compounds
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A number of arylsilane-based linkers are prepared for traceless solid-phase synthesis. General methodologies for introduction of the silyl group and various functional groups to aromatic, polyaromatic, and heteroaromatic rings are developed. Also, broad u
- Lee,Silverman
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p. 5339 - 5352
(2007/10/03)
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- Preparation of a series of substituted fluoromethylnaphthalenes
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A series of 22 3- and 4-substituted 1-fluoromethylnaphthalenes have been synthesized.Details of practical procedures for the preparation of all intermediates are described, and physical properties for all of the substituted naphthalenes synthesized, and spectral parameters for 51 previously unknown compounds, are given.
- Dixon, Elisabeth A.,Fischer, Alfred,Robinson, Frank P.
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p. 2629 - 2641
(2007/10/02)
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