- A Versatile Sub-Nanomolar Fluorescent Ligand Enables NanoBRET Binding Studies and Single-Molecule Microscopy at the Histamine H3Receptor
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The histamine H3 receptor (H3R) is considered an attractive drug target for various neurological diseases. We here report the synthesis of UR-NR266, a novel fluorescent H3R ligand. Broad pharmacological characterization revealed UR-NR266 as a sub-nanomolar compound at the H3R with an exceptional selectivity profile within the histamine receptor family. The presented neutral antagonist showed fast association to its target and complete dissociation in kinetic binding studies. Detailed characterization of standard H3R ligands in NanoBRET competition binding using UR-NR266 highlights its value as a versatile pharmacological tool to analyze future H3R ligands. The low nonspecific binding observed in all experiments could also be verified in TIRF and confocal microscopy. This fluorescent probe allows the highly specific analysis of native H3R in various assays ranging from optical high throughput technologies to biophysical analyses and single-molecule studies in its natural environment. An off-target screening at 14 receptors revealed UR-NR266 as a selective compound.
- Rosier, Niklas,Gr?tz, Lukas,Schihada, Hannes,M?ller, Jan,I?bilir, Ali,Humphrys, Laura J.,Nagl, Martin,Seibel, Ulla,Lohse, Martin J.,Pockes, Steffen
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p. 11695 - 11708
(2021/08/20)
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- Design, synthesis and biological evaluation of 2-styryl-5-hydroxy-4-pyrone derivatives and analogues as multiple functional agents with the potential for the treatment of Alzheimer's disease
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A novel series of 2-styryl-5-hydroxy-4-pyrone derivatives and analogues were designed and synthesized as H3 receptor antagonism based multitarget-directed ligands (MTDLs) for AD therapy using pharmacophore-combine strategy. The 2-styryl-5-hydro
- Hu, Chenxian,Jiang, Liu,Tang, Li,Zhang, Minkui,Sheng, Rong
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- Design, synthesis, and evaluation of some novel biphenyl imidazole derivatives for the treatment of Alzheimer's disease
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The multi-targeted organized strategy provides effectual and significant results to cure progressive neurodegenerative diseases like AD. Treatment for this awful disease is in infancy till now. A series of novel 4, 5-diphenyl-1H-imidazole linked piperazin
- Ramrao, Salunke Prashant,Shrivastava, Sushant Kumar,Tripathi, Prabhash Nath,Verma, Akash,Waiker, Digambar Kumar
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- HYPOXANTHINE COMPOUND
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PROBLEM TO BE SOLVED: To provide a novel compound having an inhibitory action of prolyl hydroxylase (PHDs) and useful as a therapeutic agent of an inflammatory bowel disease such as ulcerative colitis. SOLUTION: The present invention relates to a hypoxanthine compound represented by the following formula (I) or a pharmacologically acceptable salt thereof. The compound of the present invention or its pharmaceutically acceptable salt has an inhibitory effect of prolyl hydroxylase and is useful as a therapeutic agent for inflammatory bowel disease such as ulcerative colitis. SELECTED DRAWING: None COPYRIGHT: (C)2021,JPOandINPIT
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Paragraph 0209
(2021/07/17)
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- Controlled Reduction of Nitriles by Sodium Hydride and Zinc Chloride
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A new protocol for the controlled reduction of nitriles to aldehydes was developed using a combination of sodium hydride and zinc chloride. The iminyl zinc intermediates derived from aromatic nitriles could be further functionalized with allylmetal nucleophiles to afford homoallylamines. As the method allows the reduction of various aliphatic and aromatic nitriles with a concise procedure under milder reaction conditions and exhibits wide functional group compatibility, it is well suited for use in various opportunities in chemical synthesis.
- Chiba, Shunsuke,Ong, Derek Yiren
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p. 1369 - 1378
(2020/04/27)
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- Design, synthesis and biological evaluation of novel 4-anlinoquinazoline derivatives as EGFR inhibitors with the potential to inhibit the gefitinib-resistant nonsmall cell lung cancers
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A series of quinazoline derivatives with benzylidene hydrazine carboxamide were designed and synthesised as EGFR inhibitors. Most compounds exhibited exceptional anti-proliferative activity against A549, HepG2, MCF-7 and H1975 cells. Furthermore, six compounds demonstrated excellent inhibition activity against EGFRWT with the IC50 value both less than 2 nM. Among the six compounds, 44 exhibited the strongest activity (0.4 nM) and potently inhibited EGFRL858R/T790M (0.1 μM). Excitingly, the most potent compound 14 showed excellent enzyme inhibitory activity with 6.3 nM and 8.4 nM for both EGFRWT and EGFRT790M/L858R. The result of AO single staining and Annexin V/PI staining showed that the compound 14 and 44 could induce remarkable apoptosis of A549 cells. The compound 14 arrested the cell cycle at the S phase and compound 44 arrested the cell cycle at the G0 phase in A549 cells. These preliminary results demonstrate that compound 14 and 44 may be promising lead compound-targeting EGFR.
- Wang, Caolin,Xu, Shan,Peng, Liang,Zhang, Bingliang,Zhang, Hong,Hu, Yingying,Zheng, Pengwu,Zhu, Wufu
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p. 204 - 218
(2019/01/03)
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- Preparation and applications of phenylquinolinone-based and flavone-based derivative
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The present invention relates to a phenylquinolinone-based and flavone-based derivative and a preparation method thereof, wherein the derivative is a histamine H3 receptor antagonist, can protect andrestore the normal function of central nervous system, e
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Paragraph 0068; 0069; 0070; 0088; 0089; 0090
(2019/01/10)
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- An efficient multigram-scale synthesis of 4-(ω-chloroalkoxy)phenols
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Efficient multigram two-step syntheses of 4-(2-chloroethoxy)phenol and 4-(3-chloropropoxy)phenol in >70% yields starting from 4-hydroxybenzaldehyde and reagents with general formula Cl(CH2)nX (X = Cl, n = 2; X = OTs, n = 3) are proposed. 4-(2-Chloroethoxy)phenol can also be conveniently prepared from 4-methoxyphenol and 1,2-dichloroethane. The compounds thus obtained can be used in carbohydrate chemistry to synthesize glycosides bearing "universal" 4-(ω-chloroalkoxy)phenyl aglycons.
- Zinin,Stepanova,Jost,Kondakov,Shpirt,Chizhov,Torgov,Kononov
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p. 304 - 312
(2017/07/11)
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- Imidazolium salt-supported Mukaiyama reagent: An efficient condensation reagent for amide bond formation
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A novel imidazolium salt-supported Mukaiyama reagent (2-chloropyridinium salt) has been developed and explored as an efficient coupling agent for amide bond formation. The use of an ionic liquid-supported reagent enabled isolation of the amide products by simple extraction with organic solvents in high purity and avoiding column chromatography purification. This journal is
- Pandey, Khima,Muthyala, Manoj Kumar,Choudhary, Sunita,Kumar, Anil
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p. 13797 - 13804
(2015/02/19)
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- Design, synthesis and anticholinesterase activity of novel benzylidenechroman-4-ones bearing cyclic amine side chain
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A series of 3-(4-(aminoalkoxy)benzylidene)-chroman-4-ones 7a-r were designed and synthesized as analogs of homoisoflavonoids which are well known natural products with diverse pharmacological properties related to Alzheimer's disease. The in vitro anti-cholinesterase activity of designed compounds 7a-r against AChE and BuChE, revealed that compounds bearing piperidinylethoxy residue showed potent activity against AChE at sub-micromolar level (IC50 values = 0.122-0.207 μM), more potent than reference drug tacrine. The structure-activity relationships study of piperidinylethoxy series demonstrated that the selectivity and physicochemical properties of compounds could be optimized by selection of a proper substituent on the C-7 position of chroman ring, while the high potency of the molecule against AChE was reserved.
- Pourshojaei, Yaghoub,Gouranourimi, Ali,Hekmat, Shohre,Asadipour, Ali,Rahmani-Nezhad, Samira,Moradi, Alireza,Nadri, Hamid,Moghadam, Farshad Homayouni,Emami, Saeed,Foroumadi, Alireza,Shafiee, Abbas
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p. 181 - 189
(2015/05/20)
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- Discovery and structure-activity relationship of novel 2,3- dihydrobenzofuran-7-carboxamide and 2,3-dihydrobenzofuran-3(2 h)-one-7-carboxamide derivatives as poly(ADP-ribose)polymerase-1 Inhibitors
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Novel substituted 2,3-dihydrobenzofuran-7-carboxamide (DHBF-7-carboxamide) and 2,3-dihydrobenzofuran-3(2H)-one-7-carboxamide (DHBF-3-one-7-carboxamide) derivatives were synthesized and evaluated as inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1). A structure-based design strategy resulted in lead compound 3 (DHBF-7-carboxamide; IC50 = 9.45 μM). To facilitate synthetically feasible derivatives, an alternative core was designed, DHBF-3-one-7-carboxamide (36, IC50 = 16.2 μM). The electrophilic 2-position of this scaffold was accessible for extended modifications. Substituted benzylidene derivatives at the 2-position were found to be the most potent, with 3′,4′-dihydroxybenzylidene 58 (IC50 = 0.531 μM) showing a 30-fold improvement in potency. Various heterocycles attached at the 4′-hydroxyl/4′-amino of the benzylidene moiety resulted in significant improvement in inhibition of PARP-1 activity (e.g., compounds 66-68, 70, 72, and 73; IC50 values from 0.718 to 0.079 μM). Compound 66 showed selective cytotoxicity in BRCA2-deficient DT40 cells. Crystal structures of three inhibitors (compounds (-)-13c, 59, and 65) bound to a multidomain PARP-1 structure were obtained, providing insights into further development of these inhibitors.
- Patel, Maulik R.,Bhatt, Aaditya,Steffen, Jamin D.,Chergui, Adel,Murai, Junko,Pommier, Yves,Pascal, John M.,Trombetta, Louis D.,Fronczek, Frank R.,Talele, Tanaji T.
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p. 5579 - 5601
(2014/08/05)
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- Novel 8-(p-substituted-phenyl/benzyl)xanthines with selectivity for the A2A adenosine receptor possess bronchospasmolytic activity
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A new series of 8-(p-substituted-phenyl/benzyl)xanthines has been synthesized and evaluated in vitro for adenosine receptor binding affinity and in vivo for bronchospasmolytic effects. It was observed that the nature of substituent at para-position of 8-phenyl/benzyl group on the xanthine scaffold remarkably affects the binding affinity and selectivity of xanthine derivatives for various adenosine receptor subtypes and also their bronchospasmolytic effects. Newly synthesized 8-phenylxanthines displayed potent binding affinity and significant selectivity for A2A receptors and also produced potent bronchospasmolytic effects. Replacement of phenyl ring with benzyl moiety at C8 of xanthine skeleton resulted in notable reduction in adenosine receptor affinity and broncholytic effects.
- Yadav, Rakesh,Bansal, Ranju,Kachler, Sonja,Klotz
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p. 327 - 335
(2014/03/21)
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- Novel and highly potent histamine H3 receptor ligands. Part 3: An alcohol function to improve the pharmacokinetic profile
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Synthesis and biological evaluation of potent histamine H3 receptor antagonists incorporating a hydroxyl function are described. Compounds in this series exhibited nanomolar binding affinities for human receptor, illustrating a new possible component for the H3 pharmacophore. As demonstrated with compound BP1.4160 (cyclohexanol 19), the introduction of an alcohol function counter-intuitively allowed to reach high in vivo efficiency and favorable pharmacokinetic profile with reduced half-life.
- Labeeuw, Olivier,Levoin, Nicolas,Poupardin-Olivier, Olivia,Calmels, Thierry,Ligneau, Xavier,Berrebi-Bertrand, Isabelle,Robert, Philippe,Lecomte, Jeanne-Marie,Schwartz, Jean-Charles,Capet, Marc
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p. 2548 - 2554
(2013/06/27)
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- Determination of the binding mode and interacting amino-acids for dibasic H3 receptor antagonists
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Due to its involvement in major CNS functions, the histamine H3 receptor (H3R) is the subject of intensive medicinal chemistry investigation, supported by the range of modern drug discovery tools, such as receptor modeling and ligand docking. Although the receptor models described to date share a majority of common traits, they display discrete alternatives in amino-acid conformation, rendering ligand binding modes quite different. Such variations impede structure-based drug design in the H3R field. In the present study, we used a combination of medicinal chemistry, receptor-guided and ligand-based methods to elucidate the binding mode of antagonists. The approaches converged towards a ligand orientation perpendicular to the membrane plane, bridging Glu206 of the transmembrane helix 5 to acidic amino acids of the extracellular loops. This consensus will help future structure-based drug design for H3R ligands.
- Levoin, Nicolas,Labeeuw, Olivier,Krief, Stéphane,Calmels, Thierry,Poupardin-Olivier, Olivia,Berrebi-Bertrand, Isabelle,Lecomte, Jeanne-Marie,Schwartz, Jean-Charles,Capet, Marc
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supporting information
p. 4526 - 4529
(2013/07/26)
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- A novel Bodipy-Dipyrrin fluorescent probe: Synthesis and recognition behaviour towards Fe (II) and Zn (II)
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We present the design, synthesis, characterization and spectral studies for a new Zn (II) and Fe (II) selective fluorescent probe, 4,4-Difluoro-8-{3-[(4- phenoxy-dipyrromethene)propoxy]}-4-bora-3a,4a-diazaindacene (DPYBODPY). DPBODPY consists of a terminal fluorophore and a selective ligand and was designed to detect significant changes in absorbance and/or fluorescence on metal ion binding. The fluorophore is based on the Bodipy unit due to its excellent photophysical properties, while the dipyrrin unit has specific recognition abilities for Fe2+ and Zn2+ ions. The combination of these two structures is optimised to achieve significant spectral changes in the presence of Fe2+ and Zn2+ ions.
- Kursunlu, Ahmed Nuri,Guler, Ersin,Ucan, Halil Ismet,Boyle, Ross W.
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experimental part
p. 496 - 502
(2012/06/01)
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- Ionic liquid-supported synthesis of sulfonamides and carboxamides
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An ionic liquid-supported aldehyde was designed and converted to ionic liquid-supported secondary aryl amines through reductive amination. The reaction of ionic liquid-supported aryl amines with sulfonyl chlorides and acid chlorides, respectively, followed by cleavage using trifluoroacetic acid (TFA) afforded sulfonamides and caboxamides. To introduce additional diversity in the synthesis of sulfonamides and caboxamides, ionic liquid-supported iodosubstituted aryl amine was synthesized using the same strategy, and underwent Suzuki coupling reaction, followed by reaction with a methanesulfonyl chloride to generate the corresponding biaryl sulfonamide. The advantages of the protocol over solid-phase synthesis are homogeneous reaction medium, high loading, easy separation of products, and characterization of intermediates.
- Muthayala, Manoj Kumar,Chhikara, Bhupender S.,Parang, Keykavous,Kumar, Anil
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scheme or table
p. 60 - 65
(2012/02/04)
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- Ionic liquid-supported aldehyde: A highly efficient scavenger for primary amines
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Novel aldehyde-functionalized ionic liquids have been synthesized and used as scavengers for primary amines in the synthesis of secondary amines. The yields of secondary amines are high (82-90%) with high purity. The advantages of the protocol over that w
- Muthayala, Manoj Kumar,Kumar, Anil
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scheme or table
p. 5 - 9
(2012/02/15)
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- Synthesis and computational studies on aryloxypropyl piperazine derivatives as potential atypical antipsychotic agents
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A series of aryloxypropyl derivatives have been synthesized and evaluated for atypical antipsychotic activity in apomorphine induced mesh climbing and stereotypy assays in mice and the compounds displayed good efficacy coupled with an atypical profile. In
- Bali, Alka,Bhalla, Abhishek,Bala, Suman,Kumar, Rajesh
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scheme or table
p. 218 - 224
(2012/07/17)
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- Modification of a promiscuous inhibitor shifts the inhibition from γ-secretase to FLT-3
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The inhibition of FLT-3 activity is an interesting target for the treatment of acute myeloid leukemia (AML). The serendipitous identification of FLT-3 inhibitors from a CK1/γ-secretase programme provided compounds with dual inhibitory activity. We analyzed the structure-activity relationship of these inhibitors and derivatized them to arrive at compounds with reduced impact on γ-secretase activity and enhanced FLT-3 inhibition.
- Amombo, Ghislaine Marlyse Okala,Kramer, Thomas,Lo Monte, Fabio,Goering, Stefan,Fach, Matthias,Smith, Steven,Kolb, Stephanie,Schubenel, Robert,Baumann, Karlheinz,Schmidt, Boris
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supporting information
p. 7634 - 7640
(2013/02/21)
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- Inhibition of γ-secretase by the CK1 inhibitor IC261 does not depend on CK1δ
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CK1 and γ-secretase are interesting targets for therapeutic intervention in the treatment of cancer and Alzheimer's disease. The CK1 inhibitor IC261 was reported to inhibit γ-secretase activity. The question is: Does CK1 inhibition directly influence γ-se
- H?ttecke, Nicole,Liebeck, Miriam,Baumann, Karlheinz,Schubenel, Robert,Winkler, Edith,Steiner, Harald,Schmidt, Boris
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supporting information; experimental part
p. 2958 - 2963
(2010/08/19)
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- Low molecular weight non-peptide mimics of ω-conotoxin GVIA
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We report the synthesis and biological activity of a low molecular weight non-peptidic mimic of the analgesic peptide ω-conotoxin GVIA. The molecular weight of this compound presents a reduction by 193 g/mol compared to a previously reported lead. This co
- Duggan, Peter J.,Lewis, Richard J.,Phei Lok,Lumsden, Natalie G.,Tuck, Kellie L.,Yang, Aijun
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supporting information; experimental part
p. 2763 - 2765
(2009/12/31)
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- Onium salt supported organic synthesis in water: application to Grieco's multicomponent reaction
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By using an ammonium chloride salt as water solubilizing moiety, our onium salt supported organic synthesis strategy was extended to water as a solvent. This method allows for high loading capacities both of the supports and their solutions owing to low m
- Ouach, Aziz,Gmouh, Said,Pucheault, Mathieu,Vaultier, Michel
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p. 1962 - 1970
(2008/09/18)
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- New 1,3-dioxolane and 1,3-dioxane derivatives as effective modulators to overcome multidrug resistance
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Multidrug resistance (MDR) to antitumor agents represents a major obstacle to a successful chemotherapy of cancer. Overexpression of P-glycoprotein (p-gp) seems to be the major factor responsible for MDR. A large number of chemically unrelated compounds are known to interact with p-gp resulting in a decreasing resistance. In our efforts related to structure-activity studies of new potential MDR reversal agents we synthesized a series of compounds that differ in the aromatic core structure, the linker, and the basic moiety. For our search of new aromatic core structures we synthesized novel 2,2-diphenyl-1,3-dioxolane, 2,2- diphenyl-1,3-dioxane, and 4,5-diphenyl-1,3-dioxolane derivatives. A range of lipophilic linker structures and protonable basic moieties were synthesized and investigated to optimize the structure of the potential MDR-modulators. The compounds were tested in vitro using human Caco-2 cells. Both the cytotoxicity of the synthons and their ability to resensitize the cells were determined with a MTT assay. The results show that at low concentration various substances reverse tumor cell MDR. Some of the new structures show better effects than established modulators like trifluoperazine.
- Schmidt, Matthias,Ungvari, Johannes,Gloede, Julia,Dobner, Bodo,Langner, Andreas
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p. 2283 - 2297
(2007/10/03)
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- Identification of 2-arylbenzimidazoles as potent human histamine H4 receptor ligands
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A series of 2-arylbenzimidazoles was synthesized and found to bind with high affinity to the human histamine H4 receptor. Structure-activity relationships were investigated through library preparation and evaluation as well as traditional medicinal chemistry approaches, leading to the discovery of compounds with single-digit nanomolar affinity for the H4 receptor.
- Lee-Dutra, Alice,Arienti, Kristen L.,Buzard, Daniel J.,Hack, Michael D.,Khatuya, Haripada,Desai, Pragnya J.,Nguyen, Steven,Thurmond, Robin L.,Karlsson, Lars,Edwards, James P.,Breitenbucher, J. Guy
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p. 6043 - 6048
(2007/10/03)
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- New benzylidenethiazolidinediones as antibacterial agents
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A novel benzylidenethiazolidinedione has been discovered with antimicrobial activity. Here, we present the results of a structure-activity study on this compound with respect to its antimicrobial activity.
- Heerding, Dirk A.,Christmann, Lisa T.,Clark, Tammy J.,Holmes, David J.,Rittenhouse, Stephen F.,Takata, Dennis T.,Venslavsky, Joseph W.
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p. 3771 - 3773
(2007/10/03)
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- A new class of diamine-based human histamine H3 receptor antagonists: 4-(Aminoalkoxy)benzylamines
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4-(Aminoalkoxy)benzylamines were prepared and screened for in vitro activity at the human histamine H3 receptor. Some members of this series exhibited subnanomolar binding affinities. Analogues in which one nitrogen atom was replaced with a met
- Apodaca, Richard,Dvorak, Curt A.,Xiao, Wei,Barbier, Ann J.,Boggs, Jamin D.,Wilson, Sandy J.,Lovenberg, Timothy W.,Carruthers, Nicholas I.
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p. 3938 - 3944
(2007/10/03)
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- Synthesis of (aryloxy)alkylamines. 1. Novel antisecretory agents with H+K+-ATPase inhibitory activity
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A series of heterocyclic (aryloxy)alkylamines of structures II and III were prepared and found to possess gastric antisecretory activity. Of the variety of substituted thiazoles, benzoxazoles, and benzothiazoles prepared, thiazole 18, benzoxazole 32, and benzothiazole 47 exhibited gastric antisecretory potency comparable to that of ranitidine in vivo in the pylorous ligated rat model. In an isolated rabbit parietal system, the series of thiazoles, benzoxazoles, and benzothiazoles also demonstrated similar potency to that of ranitidine toward the inhibition of both histamine-stimulated and dcAMP-stimulated uptake of amino[14C]pyrine. These compounds inhibited the H+K+-sensitive ATPase enzyme in isolated gastric microsomes. A direct correlation existed between inhibition of 14C uptake, in vivo antisecretory activity, and inhibition of the H+K+-ATPase enzyme. The more potent antisecretory compounds 18, 32 and 47 were also the more potent enzyme inhibitors. These data suggest that the mechanism responsible for the observed in vitro and in vivo gastric antisecretory activity, in these series of compounds, is a consequence of the inhibition of the H+K+-sensitive ATPase enzyme.
- Sanfilippo,Urbanski,Press,Hajos,Shriver,Scott
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p. 1778 - 1785
(2007/10/02)
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