- Synthesis and Pharmacological Evaluation of Triazolopyrimidinone Derivatives as Noncompetitive, Intracellular Antagonists for CC Chemokine Receptors 2 and 5
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CC chemokine receptors 2 (CCR2) and 5 (CCR5) are involved in many inflammatory diseases; however, most CCR2 and CCR5 clinical candidates have been unsuccessful. (Pre)clinical evidence suggests that dual CCR2/CCR5 inhibition might be more effective in the treatment of such multifactorial diseases. In this regard, the highly conserved intracellular binding site in chemokine receptors provides a new avenue for the design of multitarget ligands. In this study, we synthesized and evaluated the biological activity of a series of triazolopyrimidinone derivatives in CCR2 and CCR5. Radioligand binding assays first showed that they bind to the intracellular site of CCR2, and in combination with functional assays on CCR5, we explored structure-affinity/activity relationships in both receptors. Although most compounds were CCR2-selective, 39 and 43 inhibited β-arrestin recruitment in CCR5 with high potency. Moreover, these compounds displayed an insurmountable mechanism of inhibition in both receptors, which holds promise for improved efficacy in inflammatory diseases.
- Ortiz Zacarías, Natalia V.,Van Veldhoven, Jacobus P. D.,Den Hollander, Lisa S.,Dogan, Burak,Openy, Joseph,Hsiao, Ya-Yun,Lenselink, Eelke B.,Heitman, Laura H.,Ijzerman, Adriaan P.
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p. 11035 - 11053
(2019/12/24)
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- Screening, synthesis, crystal structure, and molecular basis of 6-amino-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles as novel AKR1C3 inhibitors
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AKR1C3 is a promising therapeutic target for castration-resistant prostate cancer. Herein, an evaluation of in-house library discovered substituted pyranopyrazole as a novel scaffold for AKR1C3 inhibitors. Preliminary SAR exploration identified its derivative 19d as the most promising compound with an IC50 of 0.160 μM among the 23 synthesized molecules. Crystal structure studies revealed that the binding mode of the pyranopyrazole scaffold is different from the current inhibitors. Hydroxyl, methoxy and nitro group at the C4-phenyl substituent together anchor the inhibitor to the oxyanion site, while the core of the scaffold dramatically enlarges but partially occupies the SP pockets with abundant hydrogen bond interactions. Strikingly, the inhibitor undergoes a conformational change to fit AKR1C3 and its homologous protein AKR1C1. Our results suggested that conformational changes of the receptor and the inhibitor should both be considered during the rational design of selective AKR1C3 inhibitors. Detailed binding features obtained from molecular dynamics simulations helped to finally elucidate the molecular basis of 6-amino-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles as AKR1C3 inhibitors, which would facilitate the future rational inhibitor design and structural optimization.
- Zheng, Xuehua,Jiang, Zan,Li, Xiaolin,Zhang, Chen,Li, Zhe,Wu, Yinuo,Wang, Xinhua,Zhang, Chao,Luo, Hai-bin,Xu, Jun,Wu, Deyan
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supporting information
p. 5934 - 5943
(2018/11/23)
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- Synthesis of β-keto esters in-flow and rapid access to substituted pyrimidines
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We have developed an in-flow process for the synthesis of β-keto esters via the BF3·OEt2-catalyzed formal C-H insertion of ethyl diazoacetate into aldehydes. The β-keto esters were then condensed with a range of amidines to give a variety of 2,6-substituted pyrimidin-4-ols.
- Bartrum, Hannah E.,Blakemore, David C.,Moody, Christopher J.,Hayes, Christopher J.
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supporting information; experimental part
p. 8674 - 8676
(2011/03/19)
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- Highly ordered aluminium-planted mesoporous silica as active catalyst for Biginelli reaction and formyl C-H insertion reaction with diazoester
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Al-planted MCM-41s (Al-M41s) with regular mesoporous structure and Si/Al ratio of 23-32 were successfully prepared by the template-ion exchange method in which the template/Si molar ratio and Si/Al ratio were adjusted at 1.44 and 5-15, and showed much hig
- Murata, Hiroaki,Ishitani, Haruro,Iwamoto, Masakazu
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scheme or table
p. 14452 - 14455
(2011/06/17)
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- Novel synthesis of methyl ketones based on the blaise reaction
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A facile two-step synthesis of methyl ketones from alkyl nitriles via the Blaise conversion of nitriles into -keto esters and acid-mediated hydrolysis followed by decarboxylation of the resulting -keto esters is described. Copyright Taylor & Francis Group, LLC.
- Rao, H. Surya Prakash,Padmavathy,Vasantham,Rafi, Shaik
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experimental part
p. 1825 - 1834
(2009/10/02)
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- Isolation and crystal structures of both enol and keto tautomer intermediates in a hydration of an alkyne-carboxylic acid ester catalyzed by iridium complexes in water
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Hydration of tetrolic acid ethyl ester as an alkyne-carboxylic acid ester catalyzed by an Ir-aqua complex [IrIIICp*(bpy)(OH 2)]2+ (1, Cp* = η5-C 5Me5, bpy = 2,2′-bipyridine) in water provides ethyl acetoacetate as a β-keto acid ester. We report the successful isolation of both an Ir-enol tautomer intermediate [IrIIICp*(bpy){CH 3C(OH)=CC(O)OC2H5}]+ (2) and an Ir-keto tautomer intermediate [IrIIICp*(bpy){CH 3C(O)-CHC(O)OC2H5}]+ (3) in the catalytic hydration by optimizing the conditions of the isolation, such as pH of the solution, reaction time, and selection of counteranions. The structures of the enol and keto complexes with characteristic Ir-(sp2carbon) bond and Ir-(sp3 carbon) bond, respectively, were unequivocally determined by X-ray analysis, IR, electrospray ionization mass spectrometry (ESI-MS), and NMR studies including 1H, 13C, distortionless enhancement by polarization transfer (DEPT) and correlation spectroscopy (COSY) experiments. It was confirmed that the hydration of tetrolic acid ethyl ester catalyzed by 2 or 3 as initial catalysts provides ethyl acetoacetate. Mechanism of the catalytic hydration of tetrolic acid ethyl ester as an alkyne-carboxylic acid ester is discussed based on isotopic labeling experiments with the Ir-enol and Ir-keto tautomers.
- Kanemitsu, Hironobu,Uehara, Keiji,Fukuzumi, Shunichi,Ogo, Seiji
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supporting information; scheme or table
p. 17141 - 17147
(2009/04/13)
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- Affinity of 3-acyl substituted 4-quinolones at the benzodiazepine site of GABAA receptors
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The finding that alkyl 1,4-dihydro-4-oxoquinoline-3-carboxylate and N-alkyl-1,4-dihydro-4-oxoquinoline-3-carboxamide derivatives may be high-affinity ligands at the benzodiazepine binding site of the GABAA receptor, prompted a study of 3-acyl-1,4-dihydro-4-oxoquinoline (3-acyl-4-quinolones). In general, the affinity of the 3-acyl derivatives was found to be comparable with the 3-carboxylate and the 3-carboxamide derivatives, and certain substituents (e.g., benzyl) in position 6 were again shown to be important. As it is believed that the benzodiazepine binding site is situated between an α- and a γ-subunit in the GABAA receptor, selected compounds were tested on the α1β2γ2s, α2β2γ2s and α3β2γ2s GABAA receptor subtypes. The 3-acyl-4-quinolones display various degrees of selectivity for α1- versus α2- and α3-containing receptors, and high-affinity ligands essentially selective for α1 over α3 were developed.
- Lager, Erik,Nilsson, Jakob,stergaard Nielsen, Elsebet,Nielsen, Mogens,Liljefors, Tommy,Sterner, Olov
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p. 6936 - 6948
(2008/12/21)
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- Selective synthesis of α-substituted β-keto esters from aldehydes and diazoesters on mesoporous silica catalysts
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The titled reactions are effectively catalyzed on mesoporous silica MCM-41 but not on amorphous silica prepared from the same starting materials as those of MCM-41. The ordered porous structure was essential to generate the acid catalysis. Planting of Al or Ti ion improved not only the catalytic activity but also the tolerance to basic functional groups of substrates. The catalytic activity of Al- or Ti-MCM-41 was better than that of SnCl2 and NbCl5 in the homogeneous phase. In particular, Al (or Ti)-MCM-41 was characteristically active for the reaction of aldehydes with α-substituted diazoesters to give 2-substituted-3-oxo propionic acid esters.
- Murata, Hiroaki,Ishitani, Haruro,Iwamoto, Masakazu
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p. 4788 - 4791
(2008/12/22)
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- CuSO4-catalyzed diazo decomposition in water: a practical synthesis of β-keto esters
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CuSO4 was found to be an efficient catalyst for the diazo decomposition of β-hydroxy α-diazoesters in water. 1,2-H shift occurred efficiently to give β-keto esters in high yields. No O-H bond insertion products were identified.
- Liao, Mingyi,Wang, Jianbo
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p. 8859 - 8861
(2007/10/03)
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- Niobium(V) chloride-catalyzed C-H insertion reactions of α-diazoesters: Synthesis of β-keto esters
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Aldehydes react readily with ethyl diazoacetate in the presence of 5 mol% of NbCl5 in dichloromethane to produce the corresponding β-keto esters in good yields with high selectivity. This method is very useful for the preparation of β-keto esters from both electron-rich as well as electron-deficient aromatic aldehydes under mild reaction conditions.
- Yadav,Subba Reddy,Eeshwaraiah,Reddy
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p. 875 - 878
(2007/10/03)
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- Method for preparing chiral diphosphines
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The invention concerns a method for preparing a compound of formula (1) wherein: A represents naphthyl or phenyl optionally substituted; and Ar1, Ar2independently represent a saturated or aromatic carbocyclic group, optionally substituted.
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- Beta-ketoester compounds
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The beta-ketoesters of formula I are useful as precursors for organoleptic compounds, especially for flavors, fragrances and masking agents and antimicrobial compounds.
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Page column 10
(2010/11/30)
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- Beta-ketoester compounds
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The beta-ketoesters of formula I are useful as precursors for organoleptic compounds, especially for flavors, fragrances and masking agents and antimicrobial compounds.
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- Asymmetric hydrogenation method of a ketonic compound and derivative
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The present invention relates to a process for the asymmetric hydrogenation of a ketonic compound and derivative. The invention relates to the use of optically active metal complexes as catalysts for the asymmetric hydrogenation of a ketonic compound and derivative. The process for the asymmetric hydrogenation of a ketonic compound and derivative is characterized in that the asymmetric hydrogenation of said compound is carried out in the presence of an effective amount of a metal complex comprising as ligand an optically active diphosphine corresponding to one of the following formulae: STR1
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- Discovery of a series of pyrrolidine-based endothelin receptor antagonists with enhanced ET(A) receptor selectivity
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Endothelins, ET-1, ET-2, and ET-3 are potent vasoconstricting and mitogenic 21-amino acid bicyclic peptides, which exert their effects upon binding to the ET(A) and ET(B) receptors. The ET(A) receptor mediates vasoconstriction and smooth muscle cell proliferation, and the ET(B) receptor mediates different effects in different tissues, including nitric oxide release from endothelial cells, and vasoconstriction in certain vascular cell types. Selective antagonists of endothelin receptor subtypes may prove useful in determining the role of endothelin in various tissue types and disease states, and hence as therapeutic agents for such diseases. The pyrrolidine carboxylic acid A-127722 has been disclosed as a potent and ET(A)-selective antagonist, and is currently undergoing clinical trials. In our efforts to find antagonists with altered selectivity (ET(A)-selective, ET(B)-selective, or nonselective), we investigated the SAR of the 2-substituent on the pyrrolidine. Compounds with alkyl groups at the 2-position possessed ET(A) selectivity improved over A-127722 (1400-fold selective), with the best of these compounds showing nearly 19,000-fold selectivity. Copyright (C) 1999 Elsevier Science Ltd.
- Boyd, Steven A.,Mantei, Robert A.,Tasker, Andrew S.,Liu, Gang,Sorensen, Bryan K.,Henry Jr., Kenneth J.,Von Geldern, Thomas W.,Winn, Martin,Wu-Wong, Jinshyun R.,Chiou, William J.,Dixon, Douglas B.,Hutchins, Charles W.,Marsh, Kennan C.,Nguyen, Bach,Opgenorth, Terry J.
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p. 991 - 1002
(2007/10/03)
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- Simple and high yielding syntheses of β-keto esters catalysed by zeolites
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Simple and high yielding syntheses of several β-keto esters, catalysed by zeolite Hβ are reported. The methods developed include condensation of aldehydes with ethyl diazoacetate and transesterification of β-keto esters with primary, secondary, allylic and benzylic alcohols etc., all catalysed by Hβ. It was further observed that under microwave irradiation the yields of many aromatic β-keto esters were enhanced appreciably.
- Balaji,Chanda, Bhanu M.
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p. 13237 - 13252
(2007/10/03)
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- 1,2-Dithiole derivatives and therapeutic agents containing them
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Novel 1,2-dithiole-3-thione derivatives represented by general formulas (1) and (11); processes for production thereof; and therapeutic or preventive agents for diseases associated with peroxylipid, each containing said derivative as the active ingredient
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- Charge-directed conjugate addition reactions of salts of unsaturated β-keto-esters
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Strong nucleophiles undergo conjugate addition reactions with enolates of Nazarov-type reagents. Yields are strongly affected by substitution patterns and the metal cation employed.
- Cooke Jr.,Jaw
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p. 2213 - 2218
(2007/10/02)
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