- Synthesis and evaluation of new designed multiple ligands directed towards both peroxisome proliferator-activated receptor-γ and angiotensin II type 1 receptor
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Because of the complex biological networks, many pathologic disorders fail to be treated with a molecule directed towards a single target. Thus, combination therapies are often necessary, but they have many drawbacks. An alternative consists in building molecules intended to interact with multiple targets, called designed multiple ligands. We followed such a strategy in order to treat metabolic syndrome, by setting up molecules directed towards both type 1 angiotensin II (AT1) receptor and peroxisome proliferator-activated receptor-γ (PPAR-γ). For this purpose, many molecules were prepared by merging both pharmacophores following three different strategies. Their ability to activate PPAR-γ and to block AT1 receptors were evaluated in vitro. This strategy led to the preparation of many new PPAR-γ activating and AT1 blocking molecules. Among them, some exhibited both activities, highlighting the convenience of this approach.
- Meyer, Maxime,Foulquier, Sébastien,Dupuis, Fran?ois,Flament, Stéphane,Grimaud, Linda,Henrion, Daniel,Lartaud, Isabelle,Monard, Gérald,Grillier-Vuissoz, Isabelle,Boisbrun, Michel
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supporting information
p. 334 - 352
(2018/09/22)
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- Imidazole-based pinanamine derivatives: Discovery of dual inhibitors of the wild-type and drug-resistant mutant of the influenza A virus
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We previously reported potent hit compound 4 inhibiting the wild-type influenza A virus A/HK/68 (H3N2) and A/M2-S31N mutant viruses A/WS/33 (H1N1), with its latter activity quite weak. To further increase its potency, a structure-activity relationship study of a series of imidazole-linked pinanamine derivatives was conducted by modifying the imidazole ring of this compound. Several compounds of this series inhibited the amantadine-sensitive virus at low micromolar concentrations. Among them, 33 was the most potent compound, which was identified as being active on an amantadine-sensitive virus through blocking of the viral M2 ion channel. Furthermore, 33 markedly inhibited the amantadine-resistant virus (IC50 = 3.4 μM) and its activity increased by almost 24-fold compared to initial compound, with its action mechanism being not M2 channel mediated.
- Dong, Jianghong,Chen, Shengwei,Li, Runfeng,Cui, Wei,Jiang, Haiming,Ling, Yixia,Yang, Zifeng,Hu, Wenhui
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p. 605 - 615
(2015/12/30)
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- Preparation of 2-Substituted 4-Chloro-5-Formylimidazole and 5-Formylimidazole
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The invention relates to a preparation process for 2-substituted 5-formylimidazoles, wherein the intermediate high-pressurized synthesis of an 2-substituted 4-hydroxymethylimidazole as known in the art is conveniently avoided, and wherein much higher yields are obtained. Instead, it is proposed to prepare such 2-substituted 5-formylimidazoles via a one-pot synthesis involving 2-substituted 4-chloro-5-formylimidazole, thereby employing an additional hydrodehalogenation step. Moreover, it is found that the yield and purity of 2-substituted 4-chloro-5-formylimidazole itself can be significantly improved using a triflate catalyst in the preparation process.
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Page/Page column 4-5
(2008/12/08)
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- Application of high throughput screening to heterogeneous liquid and gas phase oxidation catalysis
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The application of combinatorial methods to oxidation catalysis in the liquid and gas phases is described. New lead materials have been discovered for the selective liquid phase oxidation of alcohols to aldehydes/ketones catalyzed by vanadium supported on carbon, for the low temperature CO oxidation/ light off for cold start automotive emissions control over supported noble metals and perovskites, for volatile organic compound (VOC) removal using CoCr oxide catalysts, and for the selective gas phase oxidation of propane to acrylic acid and acrylonitrile using mixed metal oxides. Catalyst discovery libraries were screened in 96-well batch reactors, in a rapid serial scanning mass spectrometer and in a massively parallel microfluidic reactor as primary screens. Promising hits were scaled up in conventional autoclaves or in multi-channel fixed bed secondary/ tertiary screening reactors.
- Guram, Anil,Hagemeyer, Alfred,Lugmair, Claus G.,Turner, Howard W.,Volpe Jr., Anthony F.,Weinberg, W. Henry,Yaccato, Karin
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p. 215 - 230
(2007/10/03)
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- Process for the preparation of formylimidazoles
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A process for the preparation of formylimidazoles of the general formula: or its tautomers, in which R1 is hydrogen or alkyl, and R2 is hydrogen, halogen or alkyl. In a first stage, an imidazole derivative of the general formula: or its tautomers, in which R1 and R2 are as defined above, is converted, by introducing an amino protective group, into an imidazole derivative of the general formula: or its tautomers, in which R3 is an amino protective group. Such derivative is formylated in a second stage in the presence of an organometallic compound and a suitable electrophile to give an imidazole derivative of the general formula: or its tautomers, in which R1, R2 and R3 are as defined above. Then, in a third stage, the end product of the formula I is obtained by cleaving off the amino protective group.
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- Process for the preparation of formylimidazoles
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A process for the catalytic conversion of hydroxymethylimidazoles to formylimidazoles. The catalysis takes place in the presence of a peroxide. Formylimidazoles are important intermediates for pharmaceutical active ingredients.
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- A New Regioselective Synthesis of 1,2,5-Trisubstituted 1H-Imidazoles and Its Application to the Development of Eprosartan
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A new method is presented for the preparation of 1,2-disubstitued-1H-imidazole-5-carboxaldehydes by the reaction of N-monosubstituted amidines with 2-halo-3-alkoxy-2-propenals. The reaction is highly regioselective with ratios of 1,2,5:1,2,4-imidazolecarboxaldehydes ranging from 85:15 to 100: 0. This methodology could be extended with similar results to the synthesis of imidazole-5-nitriles by the reaction of 2-bromo-3-methoxy-2-propenenitrile with N-monosubstituted amidines.
- Shilcrat, Susan C.,Mokhallalati, Mohamed K.,Fortunak, Joseph M. D.,Pridgen, Lendon N.
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p. 8449 - 8454
(2007/10/03)
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- N-SUBSTITUTED IMIDAZOLE AND BENZIMIDAZOLE DERIVATIVES USEFUL AS ANGIOTENSON II ANTAGONISTS
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Compounds are disclosed having the formula STR1 These compounds inhibit the action of angiotensin II and are useful, therefore, for example, as antihypertensive agents.
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- Method of producing formylimidazoles
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In producing formylimidazoles by catalytically oxidizing the corresponding 4- or 5-hydroxymethylimidazoles, the catalytic oxidation is carried out in the presence of a noble metal catalyst while oxygen or air is blown into the reaction system. In this case, it is particularly desirable that the catalytic oxidation in the presence of a noble metal catalyst be carried out in a solvent comprising an aqueous alkali or in a mixed solvent composed of an aqueous alkali and an organic solvent immiscible with water.
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- Indole- and benzimidazole-substituted imidazole and benzimidazole derivatives
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Novel compounds are disclosed having the formula STR1 wherein X, R1, R2, R3, R4, and R5 are substituents. These compounds inhibit the action of angiotensin II and are useful, therefore, for example, as antihypertensive agents.
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- Potent Nonpeptide Angiotensin II Receptor Antagonists. 2. (1-Carboxybenzyl)imidazole-5-acrylic Acids
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The further evolution of the imidazole-5-acrylic acid series of nonpeptide angiotensin II receptor antagonists is detailed (for Part 1, see: J.Med.Chem. 1992, 35, 3858).Modifications of the N-benzyl ring substitution were undertaken in an effort to mimic the Tyr4 residue of angiotensin II.Introduction of a p-carboxylic acid on the N-benzyl ring resulted in the discovery of compounds with nanomolar affinity for the receptor and good oral activity.SAR studies of these potent antagonists revealed that the thienyl ring, the (E)-acrylic acid, and the imidazole ring in addition to the two acid groups were important for high potency.Also, overlay comparisons of the parent diacid with both angiotensin II and a representative biphenylyltetrazole nonpeptide angiotensin II receptor antagonist are presented.The parent diacid analog, SKF 108566 or (E)-3--2-propenoic acid, is currently in clinical development for the treatment of hypertension.
- Keenan, Richard M.,Weinstock, Joseph,Finkelstein, Joseph A.,Franz, Robert G.,Gaitanopoulos, Dimitri E.,et al.
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p. 1880 - 1892
(2007/10/02)
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- Imidazo[1,5-d]-as-triazine-4(3H)-ones and thiones
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There is provided substituted imidazo[1,5-d]-as-triazine-4(3H)-ones and substituted imidazo[1,5-d]-as-triazin-4(3H)-thiones useful as inhibitors of the enzyme cyclic-AMP phosphodiesterase and as broad spectrum herbicides.
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- Method for the control of undesired plant species using imidazo-as-triazinones and triazine-thiones
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This disclosure describes herbicidal methods for the pre- and postemergence control of undesired mono- and dicotyledonous plants using substituted imidazo[1,5-d]-as-triazin-4(3H)-ones and substituted imidazo[1,5-d]-as-triazine-4(3H)-thiones.
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- SUBSTITUTED 3-(4-IMIDAZOLYLMETHYLENE)CARBAZIC AND THIOCARBAZIC ACID ESTERS
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There are provided substituted 3-(4-imidazolyl-methylene)carbazic acid esters and 3-(4-imidazolylmethylene)dithiocarbazic acid esters useful as intermediates for the preparation of compounds which inhibit the enzyme cyclic-AMP phosphodiesterase
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- IMIDAZO [1,5-d]-AS-TRIAZINE-4(3H)-ONES AND THIONES
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There is provided substituted imidazo[1,5-d]-as-triazine-4(3H)-ones and substituted imidazo[1,5-d]-as-triazin-4(3H)-thiones useful as inhibitors of the enzyme cyclic-AMP phosphodiesterase and as broad spectrum herbicides
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- Imidazo[1,5-d]-as-triazines
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There are provided novel substituted imidazo-[1,5-d]-as-triazines useful as hypotensive agents as well as exhibiting herbicidal activity.
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