ChemMedChem

Cover image for Vol. 5 Issue 8

August 2, 2010

Volume 5, Issue 8

Pages 1157–1403

  1. Cover Picture

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Editorial
    5. Graphical Abstract
    6. News
    7. Review
    8. Minireview
    9. Communications
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. Cover Picture: Discovery of a Class of Diketopiperazines as Antiprion Compounds (ChemMedChem 8/2010) (page 1157)

      Maria Laura Bolognesi, Hoang Ngoc Ai Tran, Matteo Staderini, Alessandra Monaco, Alberto López-Cobeñas, Salvatore Bongarzone, Xevi Biarnés, Pilar López-Alvarado, Nieves Cabezas, Maria Caramelli, Paolo Carloni, J. Carlos Menéndez and Giuseppe Legname

      Version of Record online: 23 JUL 2010 | DOI: 10.1002/cmdc.201090031

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      The cover picture shows a diketopiperazine derivative that has been found to reduce PrPSc formation in a cellular model of prion disease. Central to this disease is the conversion of the normal cellular prion protein into the abnormally folded, pathogenic species PrPSc in the brain. PrPSc aggregates, which accumulate in association with neurons in affected brain areas, are thought to be responsible of the synapse degeneration and neuronal death observed in infected hosts. The molecule was identified based on the hypothesis that planar structures may interfere with the aggregation process. The cover picture background is taken from Leonardo Da Vinci's Head Measured, and Horsemen (pen, ink and red chalk on paper), on display at the Gallerie dell'Accademia (Venice, Italy). For more information, see the Full Paper by M. L. Bolognesi et al. on p. 1324 ff.

      Corrected by:

      Corrigendum: Corrigendum: Cover Picture: Discovery of a Class of Diketopiperazines as Antiprion Compounds (ChemMedChem 8/2010)

      Vol. 5, Issue 9, 1414, Version of Record online: 30 AUG 2010

  2. Inside Cover

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Editorial
    5. Graphical Abstract
    6. News
    7. Review
    8. Minireview
    9. Communications
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. Inside Cover: Inhibition of Eimeria tenella CDK-Related Kinase 2: From Target Identification to Lead Compounds (ChemMedChem 8/2010) (page 1158)

      Kristin Engels, Carsten Beyer, Maria L. Suárez Fernández, Frank Bender, Michael Gaßel, Gottfried Unden, Richard J. Marhöfer, Jeremy C. Mottram and Paul M. Selzer

      Version of Record online: 23 JUL 2010 | DOI: 10.1002/cmdc.201090032

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      The inside cover picture shows the validated drug target EtCRK2, a cyclin-dependent kinase of Eimeria tenella homologous to human CDK2 and chicken CDK3. A potential EtCRK2 inhibitor is docked into the active site of the protein. The inset shows the intermolecular H-bonding network. The inhibitor forms a H-bond to the selectivity switch residue Glu 88 (green stick representation). The positional analogue Lys 89 of human CDK2 and chicken CDK3 is superimposed in a red, translucent stick representation. For more details, see the Full Paper by P. M. Selzer et al. on p. 1259 ff.

  3. Editorial

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Editorial
    5. Graphical Abstract
    6. News
    7. Review
    8. Minireview
    9. Communications
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. You have free access to this content
      “Hot Spots” in Medicinal Chemistry (pages 1159–1162)

      Rainer Metternich and Giorgio Tarzia

      Version of Record online: 23 JUL 2010 | DOI: 10.1002/cmdc.201000266

  4. Graphical Abstract

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Editorial
    5. Graphical Abstract
    6. News
    7. Review
    8. Minireview
    9. Communications
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. You have free access to this content
  5. News

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Editorial
    5. Graphical Abstract
    6. News
    7. Review
    8. Minireview
    9. Communications
    10. Full Papers
    11. Book Reviews
    12. Preview
  6. Review

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Editorial
    5. Graphical Abstract
    6. News
    7. Review
    8. Minireview
    9. Communications
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. Recent Advances in Endomorphin Engineering (pages 1176–1196)

      Attila Keresztes, Attila Borics and Géza Tóth

      Version of Record online: 21 MAY 2010 | DOI: 10.1002/cmdc.201000077

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      Dealing with pain: Chemically modified endomorphins with intact or increased pharmacological function and efficacy are potential painkiller candidates. Herein we summarize the achievements of the past decade regarding the design, radiolabeling, stability, and structure–activity relationships of such derivatives.

  7. Minireview

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Editorial
    5. Graphical Abstract
    6. News
    7. Review
    8. Minireview
    9. Communications
    10. Full Papers
    11. Book Reviews
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    1. Orexin Receptor Antagonists: A New Concept In CNS Disorders? (pages 1197–1214)

      John Gatfield, Catherine Brisbare-Roch, Francois Jenck and Christoph Boss

      Version of Record online: 11 JUN 2010 | DOI: 10.1002/cmdc.201000132

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      Orexin receptor antagonists are of high interest to the pharmaceutical industry. Two compounds, almorexant from Actelion Pharmaceuticals Ltd and MK-4305 from Merck & Co., are currently undergoing clinical evaluation. This Minireview summarizes recent molecular biology, pharmacology and medicinal chemistry research efforts in this field.

  8. Communications

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Editorial
    5. Graphical Abstract
    6. News
    7. Review
    8. Minireview
    9. Communications
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. Bis(7)-tacrine Derivatives as Multitarget-Directed Ligands: Focus on Anticholinesterase and Antiamyloid Activities (pages 1215–1220)

      Maria Laura Bolognesi, Manuela Bartolini, Francesca Mancini, Gianpaolo Chiriano, Luisa Ceccarini, Michela Rosini, Andrea Milelli, Vincenzo Tumiatti, Vincenza Andrisano and Carlo Melchiorre

      Version of Record online: 18 MAY 2010 | DOI: 10.1002/cmdc.201000086

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      Multitarget drug discovery is an emerging approach to the design of new drugs to treat Alzheimer's disease. Using this strategy, we developed a series of dimeric ligands derived from the lead candidate bis(7)-tacrine (1), for which a multifunctional profile has been disclosed. These derivatives were evaluated at validated targets, namely cholinesterases and amyloid production and aggregation. Compound 3 resulted more effective than 1 in inhibiting BACE-1 activity and amyloid self-aggregation.

    2. HTS and Rational Drug Design to Generate a Class of 5-HT2C-Selective Ligands for Possible Use in Schizophrenia. (pages 1221–1225)

      Alan P. Kozikowski, Sung Jin Cho, Niels H. Jensen, John A. Allen, Andreas M. Svennebring and Bryan L. Roth

      Version of Record online: 8 JUN 2010 | DOI: 10.1002/cmdc.201000186

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      Treating neurological conditions: Optimization of a previously identified lead 5-HT2C agonist (left) led to the discovery of a highly selective 5-HT2C agonist (right). Importantly, this compound is a 5-HT2B receptor antagonist. Because of its selective 5-HT2C receptor activity, the compound was further evaluated in the phencyclidine model of disrupted prepulse inhibition, and found to exhibit normalizing effects comparable to those shown by the 5-HT2C agonist vabicaserin, a drug currently in phase II clinical studies for schizophrenia.

    3. Design and Synthesis of Thiadiazoles and Thiazoles Targeting the Bcr-Abl T315I Mutant: from Docking False Positives to ATP-Noncompetitive Inhibitors (pages 1226–1231)

      Marco Radi, Emmanuele Crespan, Federico Falchi, Vincenzo Bernardo, Samantha Zanoli, Fabrizio Manetti, Silvia Schenone, Giovanni Maga and Maurizio Botta

      Version of Record online: 27 MAY 2010 | DOI: 10.1002/cmdc.201000066

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      Overcoming resistance: In an effort to optimize our previously identified dual Src/Abl hits, a new series of 1,3,4-thiadiazoles and 1,3-thiazoles were designed and synthesized, paying particular attention to the reduction of their lipophilicity and to the improvement of the affinity towards the drug-resistant T315I mutant. Compound 5 was identified as a promising allosteric inhibitor of the T315I mutant.

    4. A Structure–Activity Relationship Study of the Antimalarial and Antileishmanial Activities of Nonpeptide Macrocyclic Histone Deacetylase Inhibitors (pages 1232–1235)

      William Guerrant, Sandra C. Mwakwari, Po C. Chen, Shabana I. Khan, Babu L. Tekwani and Adegboyega K. Oyelere

      Version of Record online: 8 JUN 2010 | DOI: 10.1002/cmdc.201000087

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      Histone deacetylase inhibitors (HDACi) cause a diverse range of responses in biological systems. The depth of the antiparasitic capabilities of macrocyclic HDACi was determined against malarial and leishmanial pathogens. Antiparasitic activities of macrocyclic HDACi derived from macrolide skeletons are dependent on the length (n) of the spacer group that separates their zinc-binding and surface-recognition moieties. Antimalarial activities peak when n=6, whereas antileishmanial activities are optimum when n=8–9. This observation could facilitate the identification of other HDACi that are more selective for either parasite.

    5. Discovery of Carboranes as Inducers of 20S Proteasome Activity (pages 1236–1241)

      Hyun Seung Ban, Hidemitsu Minegishi, Kazuki Shimizu, Minako Maruyama, Yuka Yasui and Hiroyuki Nakamura

      Version of Record online: 11 MAY 2010 | DOI: 10.1002/cmdc.201000112

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      The carborane framework gives analogues able to induce 20S proteasome activities. A series of ortho-carboranylphenoxy derivatives were synthesized as 20S proteasome agonists, and carborane derivatives 11 a and 11 b were found to be potent inducers of the β1 and β2 activities of the 20S proteasome. Since small-molecule proteasome activators have not been developed, the carboranes described here have potential as chemical probes for the investigation of proteasome-dependent degradation pathways.

    6. Hit Identification and Biological Evaluation of Anticancer Pyrazolopyrimidines Endowed with Anti-inflammatory Activity (pages 1242–1246)

      Stefano Alcaro, Anna Artese, Maurizio Botta, Alessandra T. Zizzari, Francisco Orallo, Francesco Ortuso, Silvia Schenone, Chiara Brullo and Matilde Yáñez

      Version of Record online: 16 JUN 2010 | DOI: 10.1002/cmdc.201000165

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      Inhibiting COX: A small library of pyrazolopyriminines endowed with antiproliferative action was submitted to virtual screening against two COX isoforms. Three compounds were identified in silico as potentially selective COX-2 inhibitors. The biological assay confirmed one of them to be a COX-2 inhibitor with potency and selectivity comparable to known drugs.

    7. Exploring the ‘RPRL’ Motif of Apelin-13 through Molecular Simulation and Biological Evaluation of Cyclic Peptide Analogues (pages 1247–1253)

      N. J. Maximilian Macaluso and Robert C. Glen

      Version of Record online: 18 MAY 2010 | DOI: 10.1002/cmdc.201000061

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      Apelin-13 is a vasoactive peptide and one of the most potent endogenous inotropic agents identified to date. We report the design and evaluation, through extensive replica-exchange molecular dynamics and competition binding experiments, of head-to-tail cyclised analogues. This combined in silico and in vitro approach reveals that peptides promoting a β-turn at the RPRL motif show affinity for the APJ receptor, a class A G-protein-coupled receptor (GPCR) and co-receptor for HIV cellular entry.

    8. The Role of Fluorine Atoms in a Fluorinated Prostaglandin Agonist (pages 1254–1257)

      Ken-ichi Fujimura and Yoshimasa Sasabuchi

      Version of Record online: 18 MAY 2010 | DOI: 10.1002/cmdc.201000174

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      The role of covalently bound fluorine atoms in fluorinated prostaglandin agonist–receptor binding was studied using molecular dynamics and the fragment molecular orbital method. In agreement with experimental data, the simulated geometries of the fluorine and surrounding amino acid residues suggest that C[BOND]F⋅⋅⋅H and F⋅⋅⋅C[DOUBLE BOND]O interactions positively contribute to the receptor binding affinity of these ligands. The pair interaction energy profile of the fluorinated agonist confirmed these interactions. A similar profile obtained for the parent agonist suggested that the ω-chains play equivalent roles.

  9. Full Papers

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Editorial
    5. Graphical Abstract
    6. News
    7. Review
    8. Minireview
    9. Communications
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. Inhibition of Eimeria tenella CDK-Related Kinase 2: From Target Identification to Lead Compounds (pages 1259–1271)

      Kristin Engels, Carsten Beyer, Maria L. Suárez Fernández, Frank Bender, Michael Gaßel, Gottfried Unden, Richard J. Marhöfer, Jeremy C. Mottram and Paul M. Selzer

      Version of Record online: 23 JUN 2010 | DOI: 10.1002/cmdc.201000157

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      Targeting coccidiosis: Cyclin-dependant kinases (CDKs) of the protozoan parasite Eimeria tenella, which causes the severe poultry disease coccidiosis, were identified from genomic sequence data. The cell cycle and most well-characterized kinase (EtCRK2) of E. tenella were chemically validated as drug targets in enzyme and cell culture assays. Promising lead compounds were identified in a combined in silico/in vitro screening approach.

    2. Novel Monocyclam Derivatives as HIV Entry Inhibitors: Design, Synthesis, Anti-HIV Evaluation, and Their Interaction with the CXCR4 Co-receptor (pages 1272–1281)

      Sofia Pettersson, Violeta I. Pérez-Nueno, Maria Pau Mena, Bonaventura Clotet, José A. Esté, José I. Borrell and Jordi Teixidó

      Version of Record online: 8 JUN 2010 | DOI: 10.1002/cmdc.201000124

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      Novel selected monocyclam derivatives were synthesized, their in vitro anti-HIV activity was tested, and their specificity toward CXCR4 was demonstrated. Theoretical binding interactions with CXCR4 for these monocyclam derivatives were compared with those for AMD3100 and non-cyclam compounds.

    3. Facile Oxidation of Leucomethylene Blue and Dihydroflavins by Artemisinins: Relationship with Flavoenzyme Function and Antimalarial Mechanism of Action (pages 1282–1299)

      Richard K. Haynes, Wing-Chi Chan, Ho-Ning Wong, Ka-Yan Li, Wai-Keung Wu, Kit-Man Fan, Herman H. Y. Sung, Ian D. Williams, Davide Prosperi, Sergio Melato, Paolo Coghi and Diego Monti

      Version of Record online: 13 JUL 2010 | DOI: 10.1002/cmdc.201000225

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      Activity against flavoenzymes: Artemisinins may exert their antimalarial activity by disrupting the redox balance within the malaria parasite through both oxidation of FADH2 in the parasite's glutathione reductase or other parasite flavoenzymes, and by initiating oxygen-mediated autoxidation of the dihydroflavin with generation of reactive oxygen species.

    4. Synthesis, 3D-QSAR, and Structural Modeling of Benzolactam Derivatives with Binding Affinity for the D2 and D3 Receptors (pages 1300–1317)

      Laura López, Jana Selent, Raquel Ortega, Christian F. Masaguer, Eduardo Domínguez, Filipe Areias, José Brea, María Isabel Loza, Ferran Sanz and Manuel Pastor

      Version of Record online: 11 JUN 2010 | DOI: 10.1002/cmdc.201000101

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      The devil is in the details: Computational studies were carried out for a series of benzolactam derivatives with certain binding profiles for dopamine D3 and D2 receptors. Despite the high degree of homology between the D3 and D2 receptors, our approach allowed us to predict structural features related to D3/D2 affinity, as well as D3 selectivity.

    5. Modelling Inhalational Anaesthetics Using Bayesian Feature Selection and QSAR Modelling Methods (pages 1318–1323)

      David T. Manallack, Frank R. Burden and David A. Winkler

      Version of Record online: 10 JUN 2010 | DOI: 10.1002/cmdc.201000056

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      Understanding descriptor properties and descriptor selection: QSAR analysis of anaesthetics and convulsants shows the power of sparse Bayesian modelling methods, and the deficiencies of ParaSurf descriptors.

    6. Discovery of a Class of Diketopiperazines as Antiprion Compounds (pages 1324–1334)

      Maria Laura Bolognesi, Hoang Ngoc Ai Tran, Matteo Staderini, Alessandra Monaco, Alberto López-Cobeñas, Salvatore Bongarzone, Xevi Biarnés, Pilar López-Alvarado, Nieves Cabezas, Maria Caramelli, Paolo Carloni, J. Carlos Menéndez and Giuseppe Legname

      Version of Record online: 10 JUN 2010 | DOI: 10.1002/cmdc.201000133

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      Planarity is key: Thanks to a planar conformation, DKP analogues perturb PrP amyloid fibril formation in vitro. Moreover, one compound inhibits prion replication in the low micromolar range in scrapie-infected GT1 cells. Lead compounds for the further development of therapeutic agents against prion diseases, or useful chemical probes, were identified.

    7. Proteins as Possible Targets for Cytotoxic trans-Platinum(II) Complexes with Aliphatic Amine Ligands: Further Exceptions to the DNA Paradigm (pages 1335–1343)

      Leticia Cubo, Michael Groessl, Paul J. Dyson, Adoración G. Quiroga, Carmen Navarro-Ranninger and Angela Casini

      Version of Record online: 16 JUN 2010 | DOI: 10.1002/cmdc.201000104

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      The reactivity of cytotoxic trans-PtII complexes bearing aliphatic amine ligands toward a model peptide and oligonucleotides has been compared with that of cisplatin, as determined by ESI-MS. The results obtained are discussed in relation to the putative mechanism of action of this new family of promising anticancer drugs.

    8. Off-Target Effects Related to the Phosphorothioate Modification of Nucleic Acids (pages 1344–1352)

      Johannes Winkler, Martina Stessl, Jennifer Amartey and Christian R. Noe

      Version of Record online: 11 JUN 2010 | DOI: 10.1002/cmdc.201000156

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      Phosphorothioate modification: Antisense and siRNA oligonucleotides with a phosphorothioate backbone lead to decreased expression of proteins involved in apoptosis resistance and glycolytic enzymes, as well as unspecific induction of apoptosis and decreased glycolysis. This effect is linked to the phosphorothioate backbone and is independent of the mRNA target.

    9. Structure-Based Virtual Screening and Electrophysiological Evaluation of New Chemotypes of Kv1.5 Channel Blockers (pages 1353–1358)

      Qian Yang, David Fedida, Hongjian Xu, Binghe Wang, Lupei Du, Xiaojian Wang, Minyong Li and Qidong You

      Version of Record online: 10 JUN 2010 | DOI: 10.1002/cmdc.201000162

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      Molecules with heart: We undertook a structure-based virtual screening effort conducted for the discovery of new Kv1.5 channel blocker chemotypes. The scaffolds identified give rise to new hit structures for further optimization and SAR studies for the eventual development of agents more effective at treating atrial fibrillation.

    10. Synthesis and Biological Characterization of Amidopropenyl Hydroxamates as HDAC Inhibitors (pages 1359–1372)

      Florian Thaler, Mario Varasi, Andrea Colombo, Roberto Boggio, Davide Munari, Nickolas Regalia, Marco G. Rozio, Veronica Reali, Anna E. Resconi, Antonello Mai, Stefania Gagliardi, Giulio Dondio, Saverio Minucci and Ciro Mercurio

      Version of Record online: 22 JUN 2010 | DOI: 10.1002/cmdc.201000166

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      Potent and remarkably stable: Herein we summarize the synthesis and biological evaluation of a series of amidopropenyl hydroxamic acid derivatives as novel inhibitors of human histone deacetylases (HDAC). Selected compounds were studied for their in vivo pharmacokinetic behavior as well their metabolic stability in microsomal preparations and in hepatocytes.

    11. Synthesis and in vitro Evaluation of 3H-Pyrrolo[3,2-f]quinolin-9-one Derivatives That Show Potent and Selective Anti-leukemic Activity (pages 1373–1385)

      Maria Grazia Ferlin, Roberta Bortolozzi, Paola Brun, Ignazio Castagliuolo, Ernest Hamel, Giuseppe Basso and Giampietro Viola

      Version of Record online: 13 JUL 2010 | DOI: 10.1002/cmdc.201000180

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      Assembly denied: Novel substituted angular 3H-pyrrolo[3,2-f]quinolinones were synthesized as anti-tubulin agents. Biological investigations revealed very interesting structure–activity relationships regarding the position the nature of substitutions for obtaining potent and selective anti-leukemia drugs.

    12. CycloSal-phosphate Pronucleotides of Cytostatic 6-(Het)aryl-7-deazapurine Ribonucleosides: Synthesis, Cytostatic Activity, and Inhibition of Adenosine Kinases (pages 1386–1396)

      Pavla Spáčilová, Petr Nauš, Radek Pohl, Ivan Votruba, Jan Snášel, Helena Zábranská, Iva Pichová, Ria Ameral, Gabriel Birkuš, Tomáš Cihlář and Michal Hocek

      Version of Record online: 8 JUN 2010 | DOI: 10.1002/cmdc.201000192

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      Inhibiting ADK:CycloSal-phosphate prodrugs of nucleoside cytostatics (6-hetaryl-7-deazapurine ribonucleosides) were prepared. The pronucleotides display nanomolar cytostatic activities similar to those of the parent nucleosides. In addition, they exhibit pronounced inhibitory effects toward human adenosine kinase.

  10. Book Reviews

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Editorial
    5. Graphical Abstract
    6. News
    7. Review
    8. Minireview
    9. Communications
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. Ligand-Binding Assays: Development, Validation, and Implementation in the Drug Development Arena. Edited by Masood N. Khan and John W. Findlay. (page 1398)

      Claudiu Supuran

      Version of Record online: 28 MAY 2010 | DOI: 10.1002/cmdc.201000197

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      Wiley, Hoboken 2009. 424 pp., hardcover $ 110.00.—ISBN 978-0-470-04138-3

    2. A Practical Guide to Assay Development and High-Throughput Screening in Drug Discovery. Edited by Taosheng Chen. (pages 1398–1399)

      James Inglese

      Version of Record online: 23 JUN 2010 | DOI: 10.1002/cmdc.201000229

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      CRC Press, Boca Raton 2010. 291 pp., hardcover $ 159.95.—ISBN 978-1-4200-7050-7

  11. Preview

    1. Top of page
    2. Cover Picture
    3. Inside Cover
    4. Editorial
    5. Graphical Abstract
    6. News
    7. Review
    8. Minireview
    9. Communications
    10. Full Papers
    11. Book Reviews
    12. Preview
    1. Preview: ChemMedChem 9/2010 (page 1403)

      Version of Record online: 23 JUL 2010 | DOI: 10.1002/cmdc.201090035

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