Cover image for Vol. 9 Issue 11

Editor-in-Chief: Natalia Ortúzar

Impact Factor: 3.046

ISI Journal Citation Reports © Ranking: 2013: 18/58 (Chemistry Medicinal); 75/256 (Pharmacology & Pharmacy)

Online ISSN: 1860-7187

Associated Title(s): Angewandte Chemie International Edition, Chemistry - A European Journal, Chemistry – An Asian Journal, ChemBioChem, Medicinal Research Reviews, Molecular Informatics

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November 04, 2014

VIP: Design of gem-Difluoro-bis-Tetrahydrofuran as P2 Ligand for HIV-1 Protease Inhibitors to Improve Brain Penetration: Synthesis, X-ray Studies, and Biological Evaluation

VIP: Design of gem-Difluoro-bis-Tetrahydrofuran as P2 Ligand for HIV-1 Protease Inhibitors to Improve Brain Penetration: Synthesis, X-ray Studies, and Biological EvaluationHIV-1 protease plays a critical role in replication of the human immunodeficiency virus (HIV). Compounds that inhibit HIV-1 protease are an important component of combined antiretroviral therapy. Current antiretroviral therapy has significantly decreased morbidity and mortality in HIV/AIDS patients. However, there are growing concerns regarding the long-term suppression of virus replication with current therapies, given the development of drug-resistant HIV strains, as well as neurological complications. Read more...

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  1. The Discovery of a Highly Selective 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one SIRT2 Inhibitor that is Neuroprotective in an in vitro Parkinson’s Disease Model

    Dr. Paolo Di Fruscia, Emmanouil Zacharioudakis, Chang Liu, Dr. Sébastien Moniot, Sasiwan Laohasinnarong, Mattaka Khongkow, Ian F. Harrison, Konstantina Koltsida, Dr. Christopher R. Reynolds, Karin Schmidtkunz, Prof. Dr. Manfred Jung, Dr. Kathryn L. Chapman, Prof. Dr. Clemens Steegborn, Prof. David T. Dexter, Prof. Michael J. E. Sternberg, Prof. Eric W.-F. Lam and Dr. Matthew J. Fuchter

    Article first published online: 13 NOV 2014 | DOI: 10.1002/cmdc.201402431

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    Hit discovery: Through ligand-based virtual screening validation, ICL-SIRT078, a cell-active substrate-competitive SIRT2 inhibitor with a Ki value of 0.62±0.15 μM and more than 50-fold selectivity against SIRT1, 3 and 5 was identified. In addition, ICL-SIRT078 shows a significant neuroprotective effect in a lactacystin-induced model of Parkinsonian neuronal cell death in the N27 cell line. ICL-SIRT078, or an optimised derivative thereof, warrants further investigation as a neuroprotective agent in in vivo models of Parkinson’s disease.

  2. From Ergolines to Indoles: Improved Inhibitors of the Human H3 Receptor for the Treatment of Narcolepsy

    Dr. Yves P. Auberson, Dr. Thomas Troxler, Dr. Xuechun Zhang, Dr. Charles R. Yang, Dr. Dominik Feuerbach, Dr. Yu-Chih Liu, Dr. Bharat Lagu, Dr. Mark Perrone, Dr. Lijun Lei, Dr. Xiaoxia Shen, Dr. Dushan Zhang, Dr. Chunxiu Wang, Dr. Tie-Lin Wang, Dr. Karin Briner and Dr. Mark G. Bock

    Article first published online: 12 NOV 2014 | DOI: 10.1002/cmdc.201402418

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    Better than caffeine! Simplification of the ergoline scaffold of the H3 receptor antagonist 1 led to a series of indoles with improved pharmacological properties and better chemical accessibility. A combined pharmacodynamic, pharmacokinetic, and receptor occupancy evaluation led to the selection of 15 m, the wakefulness-enhancing properties of which were demonstrated by EEG measurements in rats.

  3. Oxidation Potentials of N-Modified Derivatives of the Analgesic Flupirtine Linked to Potassium KV7 Channel Opening Activity But Not Hepatocyte Toxicity

    Christian J. Lemmerhirt, Mirko Rombach, Dr. Anja Bodtke, Prof. Dr. Patrick J. Bednarski and Prof. Dr. Andreas Link

    Article first published online: 12 NOV 2014 | DOI: 10.1002/cmdc.201402442

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    Oxidation–activation–toxicity? The connection between activity, toxicity, and oxidation potential of the pain killer flupirtine was investigated. N-Modified analogues of flupirtine displayed varying oxidation potentials that appeared to be linked to potassium channel opening activity but not to in vitro hepatotoxicity. These data suggest that oxidative metabolites of flupirtine contribute to the mechanism of action, but not to liver toxicity.

  4. Evaluating p97 Inhibitor Analogues for Their Domain Selectivity and Potency against the p97–p47 Complex

    Dr. Chen-Jie Fang, Dr. Lin Gui, Dr. Xiaoyi Zhang, Derek R. Moen, Dr. Kelin Li, Dr. Kevin J. Frankowski, Dr. Henry J. Lin, Dr. Frank J. Schoenen and Dr. Tsui-Fen Chou

    Article first published online: 6 NOV 2014 | DOI: 10.1002/cmdc.201402420

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    Grade-AAA inhibitors: We carried out a structure–activity relationship study of 200 p97/valosin-containing protein inhibitor analogues for the p97 D1 and D2 domains, as well as the p97–p47 complex. Our studies provide potential starting points for the development of D1-domain-selective and p97–p47- complex-specific inhibitors.

  5. Development of Second-Generation Small-Molecule RhoA Inhibitors with Enhanced Water Solubility, Tissue Potency, and Significant in vivo Efficacy

    Sheng Ma, Dr. Jing Deng, Baoli Li, Xiujiang Li, Zhaowei Yan, Dr. Jin Zhu, Gang Chen, Prof. Zhong Wang, Prof. Hualiang Jiang, Prof. Liyan Miao and Prof. Jian Li

    Article first published online: 5 NOV 2014 | DOI: 10.1002/cmdc.201402386

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    Whoa RhoA! Second-generation small-molecule RhoA inhibitors were obtained by structural modifications to the aniline nitrogen and acid side chain of lead compounds. Among 32 compounds synthesized and tested in biological assays, one compound was identified as the most potent and water soluble, showing good in vitro and in vivo efficacy.