- Discovery of a 3-(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase Activity
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Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson's disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these indazoles led to the development of MLi-2 (1): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2.
- Scott, Jack D.,DeMong, Duane E.,Greshock, Thomas J.,Basu, Kallol,Dai, Xing,Harris, Joel,Hruza, Alan,Li, Sarah W.,Lin, Sue-Ing,Liu, Hong,Macala, Megan K.,Hu, Zhiyong,Mei, Hong,Zhang, Honglu,Walsh, Paul,Poirier, Marc,Shi, Zhi-Cai,Xiao, Li,Agnihotri, Gautam,Baptista, Marco A. S.,Columbus, John,Fell, Matthew J.,Hyde, Lynn A.,Kuvelkar, Reshma,Lin, Yinghui,Mirescu, Christian,Morrow, John A.,Yin, Zhizhang,Zhang, Xiaoping,Zhou, Xiaoping,Chang, Ronald K.,Embrey, Mark W.,Sanders, John M.,Tiscia, Heather E.,Drolet, Robert E.,Kern, Jonathan T.,Sur, Sylvie M.,Renger, John J.,Bilodeau, Mark T.,Kennedy, Matthew E.,Parker, Eric M.,Stamford, Andrew W.,Nargund, Ravi,McCauley, John A.,Miller, Michael W.
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Read Online
- Discovery of G2019S-Selective Leucine Rich Repeat Protein Kinase 2 inhibitors with in vivo efficacy
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Mutations in the Leucine Rich Repeat Protein Kinase 2 gene (LRRK2) are the most common genetic causes of Parkinson's Disease (PD). The G2019S mutation is the most common inherited LRRK2 mutation, occurs in the kinase domain, and results in increased kinase activity. We report the discovery and development of compound 38, an indazole-based, G2019S-selective (>2000-fold vs. WT) LRRK2 inhibitor capable of entering rodent brain (Kp = 0.5) and selectively inhibiting G2019S-LRRK2. The compounds disclosed herein present a starting point for further development of brain penetrant G2019S selective inhibitors that hopefully reduce lung phenotype side-effects and pave the way to providing a precision medicine for people with PD who carry the G2019S mutation.
- Fitch, William L.,Gajera, Chandresh R.,Lam, Grace,Le?niak, Robert K.,Montine, Thomas J.,Nguyen, Khanh C.,Nichols, R. Jeremy,Schonemann, Marcus,Smith, Mark,Zhao, Jing
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supporting information
(2022/01/08)
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- Design, synthesis, and Structure–Activity Relationships (SAR) of 3-vinylindazole derivatives as new selective tropomyosin receptor kinases (Trk) inhibitors
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Neurotrophic receptor tyrosine kinase (NTRK) fusions are oncogenic drivers for a variety of adult and pediatric tumors, validated by the US FDA approval of small molecular Trk inhibitors Larotrectinib (1, LOXO-101) and Entrectinib (2). However, gene mutation mediated resistance becomes a major challenge for Trk inhibitor therapies. Herein, we report the design, synthesis and Structure–Activity Relationship investigation of a series of 3-vinylindazole derivatives as new Trk inhibitors with low nanomolar potencies. A representative compound, 7mb, binds to TrkA/B/C with Kd values of 1.6, 3.1 and 4.9 nM, and suppresses their kinase functions with IC50 values of 1.6, 2.9 and 2.0 nM, respectively, but is obviously less potent for the majority of a panel of 403 wild-type kinases in a KINOMEscan selectivity investigation. The compound also potently suppresses proliferation of a panel of BaF3 cells stably transformed with NTRK fusions with IC50 values in low nM ranges. Additionally, the compound exhibits strong inhibition against the Larotrectinib-resistant cells with NTRK1-G667C or NTRK3-G696A mutations with IC50 values of 0.031 and 0.018 μM, respectively. Although the relatively poor oral bioavailability of 7mb will limit its further development, this compound may be utilized a lead molecule for further structural optimization.
- Chan, Shingpan,Ding, Ke,Duan, Yunxin,Tu, Zheng-Chao,Wang, Jie,Zhang, Zhang,Zhu, Sihua
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- AMINO PYRIMIDINE COMPOUND FOR INHIBITING PROTEIN TYROSINE KINASE ACTIVITY
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An amino pyrimidine compound for inhibiting protein tyrosine kinase activity, a pharmaceutical composition thereof, preparation therefor, and an application thereof. Specifically, an amino pyrimidine compound represented by formula (I), R1, R2, L, Y, R6, W, A, m, and n being defined in the specification, and a pharmaceutically acceptable salt, a stereoisomer, a solvent compound, a hydrate, a polymorphism, a prodrug, or an isotope variant thereof. The compound can be used for treating and/or preventing protein tyrosine kinase-related diseases such as cell proliferative diseases, cancers, and immune diseases.
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Paragraph 0413; 0414
(2019/06/07)
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- Disulfide-Catalyzed Iodination of Electron-Rich Aromatic Compounds
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Herein, a disulfide-catalyzed electrophilic iodination of aromatic compounds using 1,3-diiodo-5,5-dimethylhydantoin (DIH) has been developed. The disulfide activates DIH as a Lewis base to promote the iodination reaction in acetonitrile under mild conditions. This system is applicable to a wide range of electron-rich aromatic compounds, including acetanilide, anisole, imidazole, and pyrazole derivatives.
- Iida, Keisuke,Ishida, Shunsuke,Watanabe, Takamichi,Arai, Takayoshi
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- Disulfide-Catalyzed Iodination of Electron-Rich Aromatic Compounds
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Herein, a disulfide-catalyzed electrophilic iodination of aromatic compounds using 1,3-diiodo-5,5-dimethylhydantoin (DIH) has been developed. The disulfide activates DIH as a Lewis base to promote the iodination reaction in acetonitrile under mild conditions. This system is applicable to a wide range of electron-rich aromatic compounds, including acetanilide, anisole, imidazole, and pyrazole derivatives.
- Iida, Keisuke,Ishida, Shunsuke,Watanabe, Takamichi,Arai, Takayoshi
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p. 7411 - 7417
(2019/06/18)
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- Design, synthesis and biological evaluation of 3,5-dimethylisoxazole and pyridone derivatives as BRD4 inhibitors
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Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal (BET) family, has been recognized as an attractive candidate target for the treatment targeting gene transcription in several types of cancers. In this study, two types of novel compounds were designed, synthesized and evaluated as BRD4 inhibitors. Therein, pyridone derivatives were more effective against BRD4 protein and human leukemia cell lines MV4-11. Among them, compounds 11d, 11e and 11f were the most potential ones with IC50 values of 0.55 μM, 0.86 μM and 0.80 μM against BRD4, and exhibited remarkable antiproliferative activities against MV4-11 cells with IC50 values of 0.19 μM, 0.32 μM and 0.12 μM, respectively. Moreover, in western blot assay, compound 11e induced down-regulation of C-Myc, which is a significant downstream gene of BRD4. Cell cycle analysis assay also showed that compound 11e could block MV4-11 cells at G0/G1 phase. Taken together, our results suggested that compound 11e and its derivatives were a class of novel structural potential BRD4 inhibitors and could serve as lead compounds for further exploration.
- Rong, Juan,Feng, Zhan-Zhan,Shi, Yao-Jie,Ren, Jing,Xu, Ying,Wang, Ning-Yu,Xue, Qiang,Liu, Kun-Lin,Zhou, Shu-Yan,Wei, Wei,Yu, Luo-Ting
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- Suzuki-type cross-coupling reaction of unprotected 3-iodoindazoles with pinacol vinyl boronate: An expeditive C-3 vinylation of indazoles under microwave irradiation
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Herein we report an expeditive C-3 vinylation of unprotected 3-iodoindazoles under microwave irradiation. Ten C-5 substituted 3-vinylindazole derivatives, nine of them novel, were synthesized through this method, which proceeds in moderate to excellent yields starting from C-5 substituted 3-iodoindazole derivatives. In all cases, the C-3 vinylated derivative was the only isolated product. This methodology allows access to 3-vinylated indazoles selectively and directly without the need of N-protection. 3-Vinylindazoles could be interesting synthetic intermediates allowing access to biologically active molecules.
- Vera, Gonzalo,Diethelm, Benjamín,Terraza, Claudio A.,Recabarren-Gajardo, Gonzalo
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- THERAPEUTIC INHIBITORY COMPOUNDS
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Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds which are complement factor D inhibitors. Such compounds are useful for treating complement related disorders including, but are not limited to, autoimmune, inflammatory, and neurodegenerative diseases.
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Paragraph 00183; 00336
(2019/01/08)
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- Indazole-Based Covalent Inhibitors To Target Drug-Resistant Epidermal Growth Factor Receptor
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The specific targeting of oncogenic mutant epidermal growth factor receptor (EGFR) is a breakthrough in targeted cancer therapy and marks a drastic change in the treatment of non-small cell lung cancer (NSCLC). The recurrent emergence of resistance to these targeted drugs requires the development of novel chemical entities that efficiently inhibit drug-resistant EGFR. Herein, we report the optimization process for a hit compound that has emerged from a phenotypic screen resulting in indazole-based compounds. These inhibitors are conformationally less flexible, target gatekeeper mutated drug-resistant EGFR-L858R/T790M, and covalently alkylate Cys797. Western blot analysis, as well as characterization of the binding kinetics and kinase selectivity profiling, substantiates our approach of targeting drug-resistant EGFR-L858R/T790M with inhibitors incorporating the indazole as hinge binder.
- Tomassi, Stefano,Lategahn, Jonas,Engel, Julian,Keul, Marina,Tumbrink, Hannah L.,Ketzer, Julia,Mühlenberg, Thomas,Baumann, Matthias,Schultz-Fademrecht, Carsten,Bauer, Sebastian,Rauh, Daniel
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supporting information
p. 2361 - 2372
(2017/04/03)
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- THERAPEUTIC INHIBITORY COMPOUNDS
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Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds which are complement factor D inhibitors. Such compounds are useful for treating complement related disorders including, but are not limited to, autoimmune, inflammatory, and neurodegenerative diseases.
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Paragraph 00213
(2017/07/04)
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- Structural Optimization and Pharmacological Evaluation of Inhibitors Targeting Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases (DYRK) and CDC-like kinases (CLK) in Glioblastoma
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The DYRK family contains kinases that are up-regulated in malignancy and control several cancer hallmarks. To assess the anticancer potential of inhibitors targeting DYRK kinases, we developed a series of novel DYRK inhibitors based on the 7-azaindole scaffold. All compounds were tested for their ability to inhibit DYRK1A, DYRK1B, DYRK2, and the structurally related CLK1. The library was screened for anticancer efficacy in established and stem cell-like glioblastoma cell lines. The most potent inhibitors (IC50 ≤ 50 nM) significantly decreased viability, clonogenic survival, migration, and invasion of glioblastoma cells. Target engagement was confirmed with genetic knockdown and the cellular thermal shift assay. We demonstrate that DYRK1A’s thermal stability in cells is increased upon compound treatment, confirming binding in cells. In summary, we present synthesis, structure-activity relationship, and efficacy in glioblastoma-relevant models for a library of novel 7-azaindoles.
- Zhou, Qingqing,Phoa, Athena F.,Abbassi, Ramzi H.,Hoque, Monira,Reekie, Tristan A.,Font, Josep S.,Ryan, Renae M.,Stringer, Brett W.,Day, Bryan W.,Johns, Terrance G.,Munoz, Lenka,Kassiou, Michael
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p. 2052 - 2070
(2017/03/17)
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- THERAPEUTIC COMPOUNDS AND USES THEREOF
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The present invention relates to compounds of formula (I): and to salts thereof, wherein A has any of the values defined in the specification, and compositions and uses thereof. The compounds are useful as inhibitors of CBP and/or EP300. Also included are pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and methods of using such compounds and salts in the treatment of various CBP and/or EP300-mediated disorders.
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Page/Page column 115
(2016/05/02)
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- A novel series of indazole-/indole-based glucagon receptor antagonists
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A novel, potent series of glucagon receptor antagonists (GRAs) was discovered. These indazole- and indole-based compounds were designed on an earlier pyrazole-based GRA lead MK-0893. Structure-activity relationship (SAR) studies were focused on the C3 and C6 positions of the indazole core, as well as the benzylic position on the N-1 of indazole. Multiple potent GRAs were identified with excellent in vitro profiles and good pharmacokinetics in rat. Among them, GRA 16d was found to be orally active in blunting glucagon induced glucose excursion in an acute glucagon challenge model in glucagon receptor humanized (hGCGR) mice at 1, 3 and 10 mg/kg (mpk), and significantly lowered acute glucose levels in hGCGR ob/ob mice at 3 mpk dose.
- Lin, Songnian,Zhang, Fengqi,Jiang, Guoqiang,Qureshi, Sajjad A.,Yang, Xiaodong,Chicchi, Gary G.,Tota, Laurie,Bansal, Alka,Brady, Edward,Trujillo, Maria,Salituro, Gino,Miller, Corey,Tata, James R.,Zhang, Bei B.,Parmee, Emma R.
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p. 4143 - 4147
(2015/11/03)
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- NOVEL BI-RING PHENYL-PYRIDINES/PYRAZINES FOR THE TREATMENT OF CANCER
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The invention provides novel compounds having the general formula: wherein R1, R2 and R3 are as described herein, compositions including the compounds and methods of using the compounds.
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Page/Page column 56
(2014/07/07)
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- COMPOUNDS INHIBITING LEUCINE-RICH REPEAT KINASE ENZYME ACTIVITY
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The present invention is directed to indazole compounds which are potent inhibitors of LRRK2 kinase and useful in the treatment or prevention of diseases in which the LRRK2 kinase is involved, such as Parkinson's Disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which LRRK2 kinase is involved.
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Page/Page column 38
(2014/09/29)
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- Synthesis and antimicrobial screening of novel 3, 5-disubstituted indazole derivatives
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Amine coupling strategy was developed for the synthesis of new indazole derivatives through reaction of 4-(3- (4-hydroxyphenyl)-1-(tetrahydro-2H-pyran- 2-yl)-1H-indazol-5-yl) benzoic acid 19 with amines 20a-i. All the newly synthesized compounds were screened for their antimicrobial and antifungal activities. Among the several compounds synthesized (4-(3-(4-hydroxyphenyl)-1H- indol-5-yl)phenyl)(piperazin-1-yl)methanone 2, (4-(3-(4-hydroxyphenyl)- 1Hindazol- 5-yl)phenyl)(4-methylpiperazin-1-yl)methanone 3, 1-(4-(4-(3-(4- hydroxyphenyl)-1H-indol-5-yl) benzoyl) piperazin- 1-yl) ethanone 4 and (4-(3-(4-hydroxyphenyl)-1H-indol-5-yl) phenyl)(pyrrolidin-1-yl)methanone 9 showed potential activities against a variety of bacterial and fungal strains.
- Padmaja,Yedukondalu,Sridhar,Busi, Siddhardha,Rao, M.V. Basaveswara
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p. 625 - 631
(2013/08/23)
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- SUBSTITUTED BENZOFURAN COMPOUNDS AND METHODS OF USE THEREOF FOR THE TREATMENT OF VIRAL DISEASES
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The present invention relates to compounds of formula (I) that are useful as hepatitis C virus (HCV) NS5B polymerase inhibitors, the synthesis of such compounds, and the use of such compounds for inhibiting HCV NS5B polymerase activity, for treating or preventing HCV infections and for inhibiting HCV viral replication and/or viral production in a cell-based system.
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Page/Page column 50; 51
(2013/03/26)
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- SUBSTITUTED BENZOFURAN COMPOUNDS AND METHODS OF USE THEREOF FOR THE TREATMENT OF VIRAL DISEASES
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The present invention relates to compounds of formula (I) that are useful as hepatitis C virus (HCV) NS5B polymerase inhibitors, the synthesis of such compounds, and the use of such compounds for inhibiting HCV NS5B polymerase activity, for treating or preventing HCV infections and for inhibiting HCV viral replication and/or viral production in a cell-based system.
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Page/Page column 57; 58
(2013/03/26)
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- NOVEL COMPOUNDS THAT ARE ERK INHIBITORS
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Disclosed are the ERK inhibitors of formula (1): and the pharmaceutically acceptable salts thereof, wherein: A is a five membered monocyclic heteroaryl ring; and B is a monocyclic heterocycloalkyl ring, or a monocyclic heterocycloalkenyl ring, or a bridge
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Page/Page column 71
(2012/05/19)
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- Indazole derivatives as modulators of interleukin-1 receptor-associated kinase
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The present invention relates to modulators of IRAK kinases of formula (I) and provides compositions comprising such modulators, as well as methods therewith for treating IRAK-mediated or IRAK-associated conditions or diseases.
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Page/Page column 12
(2011/07/06)
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- Synthesis of new dehydro 2-azatryptophans and derivatives via Heck cross-coupling reactions of 3-iodoindazoles with methyl 2-(acetylamino)acrylate
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This paper describes the Heck cross-coupling reaction of 3-iodoindazoles with methyl 2-(acetylamino)acrylate as a general route to new dehydro 2-azatryptophans and protected amino acid derivatives after catalytic hydrogenation. Georg Thieme Verlag Stuttgart.
- Crestey, Francois,Collot, Valerie,Stiebing, Silvia,Rault, Sylvain
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p. 3506 - 3514
(2008/02/10)
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- Sonogashira cross-coupling reaction of 3-iodoindazoles with various terminal alkynes: A mild and flexible strategy to design 2-aza tryptamines
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This paper describes a Sonogashira-type cross-coupling reaction of 3-iodoindazoles with various terminal alkynes as a general route to 3-alkynylindazoles. The coupling reaction is illustrated by the preparation of new indazolylpropiolic or propargylic derivatives. Scope and limitation of the method are outlined.
- Arnautu, Anca,Collot, Valérie,Ros, Javier Calvo,Alayrac, Carole,Witulski, Bernhard,Rault, Sylvain
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p. 2695 - 2697
(2007/10/03)
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