- Interconversion of functional activity by minor structural alterations in nonpeptide AT2 receptor ligands
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Migration of the methylene imidazole side chain in the first reported selective drug-like AT2 receptor agonist C21/M024 (1) delivered the AT2 receptor antagonist C38/M132 (2). We now report that the AT2 receptor antagonist compound 4, a biphenyl derivative that is structurally related to 2, is transformed to the agonist 6 by migration of the isobutyl group. The importance of the relative position of the methylene imidazole and the isobutyl substituent is highlighted herein.
- Wallinder, Charlotta,Sk?ld, Christian,Botros, Milad,Guimond, Marie-Odile,Hallberg, Mathias,Gallo-Payet, Nicole,Karlén, Anders,Alterman, Mathias
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- Structure-Activity Relationship and Mode-Of-Action Studies Highlight 1-(4-Biphenylylmethyl)-1H-imidazole-Derived Small Molecules as Potent CYP121 Inhibitors
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CYP121 of Mycobacterium tuberculosis (Mtb) is an essential target for the development of novel potent drugs against tuberculosis (TB). Besides known antifungal azoles, further compounds of the azole class were recently identified as CYP121 inhibitors with
- Walter, Isabell,Adam, Sebastian,Gentilini, Maria Virginia,Kany, Andreas M.,Brengel, Christian,Thomann, Andreas,Sparwasser, Tim,K?hnke, Jesko,Hartmann, Rolf W.
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p. 2786 - 2801
(2021/06/27)
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- Single Peptide Backbone Surrogate Mutations to Regulate Angiotensin GPCR Subtype Selectivity
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Mutating the side-chains of amino acids in a peptide ligand, with unnatural amino acids, aiming to mitigate its short half-life is an established approach. However, it is hypothesized that mutating specific backbone peptide bonds with bioisosters can be exploited not only to enhance the proteolytic stability of parent peptides, but also to tune its receptor subtype selectivity. Towards this end, four [Y]6-Angiotensin II analogues are synthesized where amide bonds have been replaced by 1,4-disubstituted 1,2,3-triazole isosteres in four different backbone locations. All the analogues possessed enhanced stability in human plasma in comparison with the parent peptide, whereas only two of them achieved enhanced AT2R/AT1R subtype selectivity. This diversification has been studied through 2D NMR spectroscopy and unveiled a putative more structured microenvironment for the two selective ligands accompanied with increased number of NOE cross-peaks. The most potent analogue, compound 2, has been explored regarding its neurotrophic potential and resulted in an enhanced neurite growth with respect to the established agent C21.
- Vrettos, Eirinaios I.,Valverde, Ibai E.,Mascarin, Alba,Pallier, Patrick N.,Cerofolini, Linda,Fragai, Marco,Parigi, Giacomo,Hirmiz, Baydaa,Bekas, Nick,Grob, Nathalie M.,Stylos, Evgenios Κ.,Shaye, Hamidreza,Del Borgo, Mark,Aguilar, Marie-Isabel,Magnani, Francesca,Syed, Nelofer,Crook, Timothy,Waqif, Emal,Ghazaly, Essam,Cherezov, Vadim,Widdop, Robert E.,Luchinat, Claudio,Michael-Titus, Adina T.,Mindt, Thomas L.,Tzakos, Andreas G.
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supporting information
p. 10690 - 10694
(2020/07/25)
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- Derisking the Cu-Mediated 18F-Fluorination of Heterocyclic Positron Emission Tomography Radioligands
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Molecules labeled with fluorine-18 (18F) are used in positron emission tomography to visualize, characterize and measure biological processes in the body. Despite recent advances in the incorporation of 18F onto arenes, the development of general and efficient approaches to label radioligands necessary for drug discovery programs remains a significant task. This full account describes a derisking approach toward the radiosynthesis of heterocyclic positron emission tomography (PET) radioligands using the copper-mediated 18F-fluorination of aryl boron reagents with 18F-fluoride as a model reaction. This approach is based on a study examining how the presence of heterocycles commonly used in drug development affects the efficiency of 18F-fluorination for a representative aryl boron reagent, and on the labeling of more than 50 (hetero)aryl boronic esters. This set of data allows for the application of this derisking strategy to the successful radiosynthesis of seven structurally complex pharmaceutically relevant heterocycle-containing molecules.
- Taylor, Nicholas J.,Emer, Enrico,Preshlock, Sean,Schedler, Michael,Tredwell, Matthew,Verhoog, Stefan,Mercier, Joel,Genicot, Christophe,Gouverneur, Véronique
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supporting information
p. 8267 - 8276
(2017/06/27)
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- Structure-based optimization leads to the discovery of NSC765844, a highly potent, less toxic and orally efficacious dual PI3K/mTOR inhibitor
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The phosphoinositide 3-kinase (PI3K) family is one of the most frequently activated enzymes in a wide range of human cancers; thus, inhibition of PI3K represents a promising strategy for cancer therapy. Herein, a series of benzylamine substituted arylsulfonamides were designed and synthesized as dual PI3K/mTOR inhibitors using a strategy integrating focused library design and virtual screening, resulting in the discovery of 13b (NSC765844). The compound 13b exhibits highly potent enzyme inhibition with IC50s of 1.3, 1.8, 1.5, 3.8 and 3.8?nM for PI3Kα, β, γ, δ, and mTOR, respectively. 13b was further evaluated in NCI by an in?vitro cytotoxic screening program. Broad-spectrum antitumor activities with mean GI50value of 18.6?nM against approximately 60 human tumor cell lines were found. 13b displayed favorable physicochemical properties and superior pharmacokinetic profiles for animal studies. It significantly inhibited tumor growth when administered orally in an A549 non-small-cell lung carcinoma xenograft and BEL7404 human hepatocellular carcinoma xenograft models. On the basis of its excellent in?vivo efficacy and superior pharmacokinetic profiles, 13b has been selected for further preclinical investigation as a promising anticancer drug candidate.
- Han, Jinsong,Chen, Ying,Yang, Chao,Liu, Ting,Wang, Mingping,Xu, Haojie,Zhang, Ling,Zheng, Canhui,Song, Yunlong,Zhu, Ju
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p. 684 - 701
(2016/07/21)
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- Synthesis of 11C-labeled Sulfonyl Carbamates through a Multicomponent Reaction Employing Sulfonyl Azides, Alcohols, and [11C]CO
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We describe the development of a new methodology focusing on 11C-labeling of sulfonyl carbamates in a multicomponent reaction comprised of a sulfonyl azide, an alkyl alcohol, and [11C]CO. A number of 11C-labeled sulfonyl carbamates were synthesized and isolated, and the developed methodology was then applied in the preparation of a biologically active molecule. The target compound was obtained in 24±10 % isolated radiochemical yield and was evaluated for binding properties in a tumor cell assay; in vivo biodistribution and imaging studies were also performed. This represents the first successful radiolabeling of a non-peptide angiotensin II receptor subtype 2 agonist, C21, currently in clinical trials for the treatment of idiopathic pulmonary fibrosis.
- Stevens, Marc Y.,Chow, Shiao Y.,Estrada, Sergio,Eriksson, Jonas,Asplund, Veronika,Orlova, Anna,Mitran, Bogdan,Antoni, Gunnar,Larhed, Mats,?berg, Ola,Odell, Luke R.
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p. 566 - 573
(2016/12/22)
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- Anti-Plasmodium activity of imidazolium and triazolium salts
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We have previously reported that tetrazolium salts were both potent and specific inhibitors of Plasmodium replication, and that they appear to interact with a parasite component that is both essential and conserved. The use of tetrazolium salts in vivo is limited by the potential reduction of the tetrazolium ring to form an inactive, neutral acyclic formazan. To address this issue imidazolium and triazolium salts were synthesized and evaluated as Plasmodium inhibitors. Many of the imidazolium and triazolium salts were highly potent with active concentrations in the nanomolar range in Plasmodium falciparum cultures, and specific to Plasmodium with highly favorable therapeutic ratios. The results corroborate our hypothesis that an electron-deficient core is required so that the compound may thereby interact with a negatively charged moiety on the parasite merozoite; the side groups in the compound then form favorable interactions with adjacent parasite components and thereby determine both the potency and selectivity of the compound.
- Vlahakis, Jason Z.,Lazar, Carmen,Crandall, Ian E.,Szarek, Walter A.
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experimental part
p. 6184 - 6196
(2010/09/14)
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- Synthesis, Biological Evaluation, and Molecular Modeling of 1 -Benzyl-1H-imidazoles as Selective Inhibitors of Aldosterone Synthase (CYP11B2)
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Reducing aldosterone action is beneficial in various major diseases such as heart failure. Currently, this is achieved, with mineralocorticoid, receptor antagonists, however, aldosterone synthase (CYP 11B2) inhibitors may offer a promising alternative. In this study, we used three-dimensional modeling of CYP11B2 to model, the binding modes of the natural substrate 18-hydroxycorticosterone and the recently published CYP11B2 inhibitor R-fadrozole as a rational guide to design 44 structurally simple and achiral 1-benzyl-1H-imidazoles. Their syntheses, in vitro inhibitor potencies, and in silico docking are described. Some promising CYP11B2 inhibitors were identified, with our novel lead, MOERAS 115 (4-((5-phenyl-1H-imidazol-1-yl)methyl) benzonitrile) displaying an IC50 for CYP11B2 of 1.7 nM, and a CYP11B2 (versus CYP11B1) selectivity of 16.5, comparable to R-fadrozole (IC 50 for CYP11B26.0 nM, selectivity 19.8). Molecular docking of the inhibitors in the models enabled us to generate posthoc hypotheses on their binding modes, providing a valuable basis for future studies and further design of CYP11B2 inhibitors.
- Roumen, Luc,Peeters, Joris W.,Emmen, Judith M. A.,Beugels, Ilona P. E.,Custers, Erica M. G.,De Gooyer, Marcel,Plate, Ralf,Pieterse, Koen,Hilbers, Peter A. J.,Smits, Jos F. M.,Vekemans, Jef A. J.,Leysen, Dirk,Ottenheijm, Harry C. J.,Janssen, Henk M.,Rob Hermans
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experimental part
p. 1712 - 1725
(2010/07/17)
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- Synthesis, biological evaluation and molecular modelling studies of methyleneimidazole substituted biaryls as inhibitors of human 17α-hydroxylase-17,20-lyase (CYP17). Part I: Heterocyclic modifications of the core structure
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Novel chemical entities were prepared via Suzuki and SN reaction as AC-ring substrate mimetics of CYP17. The synthesised compounds 1-31 were tested for activity using human CYP17 expressed in Escherichia coli. Promising compounds were tested for selectivity against hepatic CYP enzymes (3A4, 2D6, 1A2, 2C9, 2C19, 2B6). Two potent inhibitors (27, IC50 = 373 nM/28, IC50 = 953 nM) were further examined in rats regarding their effects on plasma testosterone levels and their pharmacokinetic properties. Compound 28 was similarly active as abiraterone and showed better pharmacokinetic properties (higher bioavailability, t1/2 9.5 h vs 1.6 h). Docking studies revealed two new binding modes different from the one of the substrates and steroidal inhibitors.
- Jagusch, Carsten,Negri, Matthias,Hille, Ulrike E.,Hu, Qingzhong,Bartels, Marc,Jahn-Hoffmann, Kerstin,Mendieta, Mariano A.E. Pinto-Bazurco,Rodenwaldt, Barbara,Mueller-Vieira, Ursula,Schmidt, Dirk,Lauterbach, Thomas,Recanatini, Maurizio,Cavalli, Andrea,Hartmann, Rolf W.
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p. 1992 - 2010
(2008/09/20)
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- Synthesis and biochemical evaluation of a range of potent benzyl imidazole-based compounds as potential inhibitors of the enzyme complex 17α-hydroxylase/17,20-lyase (P45017α)
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The cytochrome P-450 enzyme, 17α-hydroxylase/17,20-lyase (P45017α), is a potential target in hormone-dependent cancers. Here, we report the synthesis and biochemical evaluation of a range of benzyl imidazole-based compounds which have been targeted against the two components of this enzyme, that is, 17α-hydroxylase (17α-OHase) and 17,20-lyase (lyase). The results from the biochemical testing suggest that the compounds synthesised are good inhibitors, with N-4-iodobenzyl imidazole (5) (IC50 = 10.06 μM against 17α-OHase and IC50 = 1.58 μM against lyase) showing equipotent activity against lyase compared to the standard compound, ketoconazole (KTZ) (IC50 = 3.76 ± 0.01 μM against 17α-OHase and IC50 = 1.66 ± 0.15 μM against lyase). Furthermore, the compounds tested are less potent towards the 17α-OHase component, a desirable property in the development of novel inhibitors of P45017α.
- Owen, Caroline P.,Dhanani, Sachin,Patel, Chirag H.,Shahid, Imran,Ahmed, Sabbir
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p. 4011 - 4015
(2007/10/03)
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- Synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a range of 4-substituted phenyl alkyl imidazole-based inhibitors of the enzyme complex 17α-hydroxylase/17,20-lyase (P45017α)
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We report the preliminary results of the synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a number of phenyl alkyl imidazole-based compounds as inhibitors of the two components of 17α-hydroxylase/17,20-lyase (P45017α), that is, 17α-hydroxylase (17α-OHase) and 17,20-lyase (lyase). The results show that N-3-(4-bromophenyl) propyl imidazole (12) (IC50 = 2.95 μM against 17α-OHase and IC50 = 0.33 μM against lyase) is the most potent compound within the current study, in comparison to ketoconazole (KTZ) (IC50 = 3.76 μM against 17α-OHase and IC50 = 1.66 μM against lyase). Modelling of these compounds suggests that the length of the alkyl chain enhances the interaction between the inhibitor and the area of the active site corresponding to the C(3) area of the steroid backbone, thereby increasing potency.
- Patel, Chirag H.,Dhanani, Sachin,Owen, Caroline P.,Ahmed, Sabbir
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p. 4752 - 4756
(2007/10/03)
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- Syntheses and crystal structures of 1D tubular chains and 2D polycatenanes built from the asymmetric 1-(1-imidazolyl)-4-(imidazol-1-ylmethyl)benzene ligand with metal salts
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Reactions of a new asymmetric ligand, 1-(1-imidazolyl)-4-(imidazol-1- ymethyl)benzene (IIMB), with various metal [Cd(II), Mn(II), Zn(II)] salts led to the formation of molecular, one- (1D) and two-dimensional (2D) architectures [Cd(IIMB)2(H2O)(SO4)]·7.5H2O 1, [Cd(IIMB)2Cl2]·H2O 2, [Cd(IIMB) 4(H2O)2](NO3)2-5H 2O 3, [Cd(IIMB)(OAc)2]·H2O 4, [Mn(IIMB)2(SO4)(H2O)]·8.2H2O 5, [Mn(IIMB)4(H2O)2]Cl2· 5H2O 6 and [Zn(IIMB)2]4(NO3) 8·13.5H2O 7. All the structures were established by single-crystal X-ray diffraction analysis. Both compounds 1 and 5 with sulfate anion are 2D polycatenanes formed by the interlocking of 1D double-stranded chains, while 2 and 4 with chloride and acetate anions are 1D chains. The results provide nice examples of topologies of metal-organic frameworks controlled by the counter anions. Interestingly, 3 and 6 are discrete molecular complexes with monometallic cores and form 2D networks through strong intermolecular hydrogen bonds. Complex 7, obtained under the same conditions as 3, is a 1D tubular chain. The structural difference between 3 and 7 suggests the metal ions also have a significant effect on the construction of supramolecular architectures. Furthermore, the photoluminescence properties of these compounds were investigated in the solid state at room temperature.
- Zhu, Hui-Fang,Zhao, Wei,Okamura, Taka-Aki,Fan, Jian,Sun, Wei-Yin,Ueyama, Norikazu
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p. 1010 - 1018
(2007/10/03)
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- Design, synthesis, and biological evaluation, of the first selective nonpeptide AT2 receptor agonist
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The first druglike selective angiotensin II AT2 receptor agonist (21) with a Ki value of 0.4 nM for the AT2 receptor and a Ki > 10 μM for the AT1 receptor is reported. Compound 21, with a bioavailability of 20-3
- Wan, Yiqian,Wallinder, Charlotta,Plouffe, Bianca,Beaudry, Hélène,Mahalingam,Wu, Xiongyu,Johansson, Berndt,Holm, Mathias,Botoros, Milad,Karlén, Anders,Pettersson, Anders,Nyberg, Fred,F?ndriks, Lars,Gallo-Payet, Nicole,Hallberg, Anders,Alterman, Mathias
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p. 5995 - 6008
(2007/10/03)
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