ChemMedChem

Cover image for Vol. 12 Issue 2

Editorial Board Chairs: Antonello Mai, Rainer Metternich. Assoc. Editors: David Peralta, Scott Williams (Sr)

Impact Factor: 2.98

ISI Journal Citation Reports © Ranking: 2015: 18/59 (Chemistry Medicinal); 77/255 (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

The Big 10 for ChemMedChem

10th Anniversary

In 2016, ChemMedChem celebrates its 10th anniversary. As part of the celebration, watch out for:

ChemMedChem: Past and Future

Past and present Editorial Board Chairmen Giorgio Tarzia, Antonello Mai and Rainer Metternich share their thoughts on the history of the journal, as well as where the field of medicinal chemistry is headed in this ChemistryViews interview

Access these top articles for free in 2016:

Anniversary Articles: Essays, Viewpoints, and Reviews

Leading medicinal chemists, some of which are ChemMedChem editorial and international advisory board members, share their thoughts on their specializations and the field of medicinal chemistry in general.

Immune by Heart: Unexpected Observations Inspiring Perspective Therapeutic/Preventive Strategies against Cancer

Immune by Heart: Unexpected Observations Inspiring Perspective Therapeutic/Preventive Strategies against Cancer

Filippo Minutolo*

Why is the heart substantially immune to cancer? Why do certain dwarf populations have a lower incidence of tumors? Why do plants get cancer but no metastases? These and other observations warrant greater consideration by the scientific community, as they might lead to innovative approaches to tackle cancer.

ChemMedChem 10.1002/cmdc.201600483 [Viewpoints]

Recent Developments Using Small Molecules to Target RAD51: How to Best Modulate RAD51 for Anticancer Therapy?

Recent Developments Using Small Molecules to Target RAD51: How to Best Modulate RAD51 for Anticancer Therapy?

Brian Budke, Wei Lv, Alan P. Kozikowski, Philip P. Connell*

RAD51 and anticancer therapy: RAD51 is an attractive cancer therapeutic target. Currently, a number of RAD51 inhibitory/stimulatory compounds have been identified with potential applications in cancer therapy. Herein we provide a short review of recent developments in this area together with our perspective on how to develop small molecules that modulate the biological activity of RAD51 for anticancer therapy.

ChemMedChem 10.1002/cmdc.201600426 [Viewpoints]

The Use of Thermodynamic and Kinetic Data in Drug Discovery: Decisive Insight or Increasing the Puzzlement?

The Use of Thermodynamic and Kinetic Data in Drug Discovery: Decisive Insight or Increasing the Puzzlement?

Gerhard Klebe*

The success of hit-to-lead-to-drug optimization in drug discovery is rated primarily by binding affinity, and rational approaches try to relate this property with structure. This Viewpoint assesses our current understanding of thermodynamics–or kinetics–structure relationships and questions the accuracy of data collected to learn about the thermodynamic and kinetic basis to comprehend affinity.

ChemMedChem 2015, 10, No. 2, 229–231 [Viewpoint]

How Many Molecules Does It Take to Tell a Story? Case Studies, Language, and an Epistemic View of Medicinal Chemistry

How Many Molecules Does It Take to Tell a Story? Case Studies, Language, and an Epistemic View of Medicinal Chemistry

Martin Stahl*, Sabine Baier

If we were to visualize the evolutionary growth of medicinal chemistry over time and across target families, molecule by molecule, what picture would emerge? Do we have adequate language to describe the research process?

ChemMedChem 2015, 10, No. 6, 949–956 [Essay]

Medicinal Chemists of the 21st Century—Who Are We and Where to Go?

Medicinal Chemists of the 21st Century—Who Are We and Where to Go?

Peter Nussbaumer*

The art and science to craft good drugs require an ever-growing plethora of skills from a medicinal chemist. To ensure sustained quality and achievements, we need to focus on superior design without excluding complex structures a priori, to proactively shape the future of our discipline, to discuss specialization, to intensify exchange between academia and industry, and to remodel education of the next generations of medicinal chemists.

ChemMedChem 2015, 10, No. 7, 1133–1139 [Viewpoint]

Glycans in Medicinal Chemistry: An Underexploited Resource

Glycans in Medicinal Chemistry: An Underexploited Resource

Alberto Fernández-Tejada*, F. Javier Cañada, Jesús Jiménez-Barbero*

Keeping drug discovery sweet! Glycans are an important, though underexploited, platform in medicinal chemistry. Here, relevant examples are used to highlight the potential of oligosaccharides in chemistry, biology, and medicine. Key research and development trends in glycoscience, including carbohydrate-derived drugs, vaccines and therapeutic glycoproteins, are summarized with a view towards future, promising directions in the field for drug discovery purposes and biomedical applications.

ChemMedChem 2015, 10, No. 8, 1291–1295 [Viewpoint]

A Bright Future for Evolutionary Methods in Drug Design

A Bright Future for Evolutionary Methods in Drug Design

Tu C. Le, David A. Winkler*

Drug-like chemical space is extremely large, essentially infinite. Evolutionary algorithms are very effective ways to explore large spaces and to identify novel molecules with useful biological properties. The emergence of new technologies like automated chemical synthesis and robotic screening has removed the major barriers to much wider application of these ingenious and efficient evolutionary methods in drug discovery. (Image reproduced with permission. Copyright Randal S. Olson, Wikimedia Commons.)

ChemMedChem 2015, 10, No. 8, 1296–1300 [Viewpoint]

Prospects of β-Secretase Inhibitors for the Treatment of Alzheimer’s Disease

Prospects of β‐Secretase Inhibitors for the Treatment of Alzheimer’s Disease

Arun K. Ghosh*, Jordan Tang

Hitting a key target: β-Secretase is an attractive drug design target for the treatment of Alzheimer’s disease (AD). This enzyme plays an important role in the production of neurotoxic β-amyloid peptide in the brain. A number of β-secretase (BACE1) inhibitors have recently entered into preclinical trials. One drug has advanced to phase II/III clinical development. Herein we discuss our viewpoint on BACE1 inhibitors for the treatment of AD patients.

ChemMedChem 2015, 10, No. 9, 1463–1466 [Viewpoint]

The Role of Target Binding Kinetics in Drug Discovery

The Role of Target Binding Kinetics in Drug Discovery

Dong Guo, Laura H. Heitman, Adriaan P. IJzerman*

Joining forces: The combination of structure–affinity relationships and structure–kinetics relationships is the emerging strategy in hit-to-lead optimization. Herein we propose a scheme that is expected to aid in the design and discovery of candidate compounds with desired kinetics profiles. Improved evaluation protocols to predict drug efficacy and safety can be formulated with more kinetics-directed research.

ChemMedChem 2015, 10, No. 11, 1793–1796 [Viewpoint]

Computational Chemistry in the Pharmaceutical Industry: From Childhood to Adolescence

Computational Chemistry in the Pharmaceutical Industry: From Childhood to Adolescence

Alexander Hillisch*, Nikolaus Heinrich, Hanno Wild

Computational chemistry impact: Computational chemistry in pharmaceutical industry has matured to a highly productive technique with a clear impact on clinical development pipelines. Excessive expectations from the past have now given way to realistic applications. We describe our view on important organizational and methodological success factors and future developments in computational medicinal chemistry.

ChemMedChem 2015, 10, No. 12, 1958–1962 [Viewpoint]

We Need 2C but Not 2B: Developing Serotonin 2C (5-HT2C) Receptor Agonists for the Treatment of CNS Disorders

We Need 2C but Not 2B: Developing Serotonin 2C (5‐HT2C) Receptor Agonists for the Treatment of CNS Disorders

Jianjun Cheng, Alan P. Kozikowski*

We need 2C but not 2B: The 5-HT2C receptor has emerged as a potential drug target in the treatment of a variety of central nervous system (CNS) disorders. The design of highly selective 5-HT2C agonists lacking 5-HT2B agonism is one of the most important goals for drug discovery in this field. Recent developments in the design of selective 5-HT2C agonists are summarized, and future directions are proposed.

ChemMedChem 2015, 10, No. 12, 1963–1967 [Viewpoint]

Inspired by Nature: The 3-Halo-4,5-dihydroisoxazole Moiety as a Novel Molecular Warhead for the Design of Covalent Inhibitors

Inspired by Nature: The 3‐Halo‐4,5‐dihydroisoxazole Moiety as a Novel Molecular Warhead for the Design of Covalent Inhibitors

Andrea Pinto, Lucia Tamborini, Gregorio Cullia, Paola Conti, Carlo De Micheli*

A hint from Nature: 3-Halo-4,5-dihydroisoxazole, a component of the naturally occurring antibiotic acivicin, is a powerful warhead for the covalent inhibition of target enzymes. Here, we describe the use of this moiety in medicinal chemistry to develop covalent inhibitors of parasitic and bacterial enzymes, and human targets involved in the modulation of neuronal metabolic pathways or tumor cell metabolism.

ChemMedChem 2016, 11, No. 1, 10–14 [Concept]

Why Hydroxamates May Not Be the Best Histone Deacetylase Inhibitors—What Some May Have Forgotten or Would Rather Forget?

Why Hydroxamates May Not Be the Best Histone Deacetylase Inhibitors—What Some May Have Forgotten or Would Rather Forget?

Sida Shen, Alan P. Kozikowski*

Hydroxamates and mutagenicity: Hydroxamate-based histone deacetylase inhibitors have been approved as therapeutic agents for use in oncology applications. Concern is now emerging that the potential mutagenicity of hydroxamates would present a significant obstacle in using these compounds in other clinical applications. Herein we summarize mechanistic issues surrounding their mutagenicity and discuss some ways of getting around this problem.

ChemMedChem 2016, 11, No. 1, 15–21 [Viewpoint]

Designing Irreversible Inhibitors—Worth the Effort?

Designing Irreversible Inhibitors—Worth the Effort?

Concepción González-Bello*

No backing out: For many years, medicinal chemists have generally steered clear of irreversible inhibitors, given the relatively high risk they pose in terms of off-target effects. However, the unique benefits of irreversible inhibition are gathering more attention, as further knowledge is gained about the challenging mechanisms behind covalent modification for certain compound classes.

ChemMedChem 2016, 11, No. 1, 22–30 [Minireview]

Broadly Neutralizing Antibody-Guided Carbohydrate-Based HIV Vaccine Design: Challenges and Opportunities

Broadly Neutralizing Antibody‐Guided Carbohydrate‐Based HIV Vaccine Design: Challenges and Opportunities

Chang-Cheng Liu, Xiu-Jing Zheng, Xin-Shan Ye*

Anti-HIV glycoconjugates: Broadly neutralizing antibodies provide conserved glycan epitopes of HIV, which can guide the design of vaccines. Many carbohydrate-based vaccines have been designed, but none have succeeded in practice thus far. Herein we review new strategies toward the design of high-affinity antigens and immunization regimens that have been proposed and tested.

ChemMedChem 2016, 11, No. 4, 357–362 [Minireview]

Some of our Hottest Papers from the Past Year

Bisamidate Prodrugs of 2-Substituted 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA, adefovir) as Selective Inhibitors of Adenylate Cyclase Toxin from Bordetella pertussis

Bisamidate Prodrugs of 2‐Substituted 9‐[2‐(Phosphonomethoxy)ethyl]adenine (PMEA, adefovir) as Selective Inhibitors of Adenylate Cyclase Toxin from Bordetella pertussis

Michal Česnek, Petr Jansa, Markéta Šmídková*, Helena Mertlíková-Kaiserová, Martin Dračínský, Tarsis F. Brust, Petr Pávek, František Trejtnar, Val J. Watts, Zlatko Janeba*

Whooping cough combatted: With the aim to establish a new strategy against pertussis, C2-modified adefovir analogues in their bisamidate prodrug form were found to efficiently inhibit adenylate cyclase toxin (ACT) from Bordetella pertussis. The compounds show favorable plasma stability, effective distribution to target tissues, and good selectivity for ACT over human adenylate cyclase isoforms.

ChemMedChem 2015, 10, No. 8, 1351–1364 [Full Paper]

Discovery, Synthesis, and Optimization of Diarylisoxazole-3-carboxamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore

Discovery, Synthesis, and Optimization of Diarylisoxazole‐3‐carboxamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore

Sudeshna Roy, Justina Šileikytė, Marco Schiavone, Benjamin Neuenswander, Francesco Argenton, Jeffrey Aubé, Michael P. Hedrick, Thomas D. Y. Chung, Michael A. Forte*, Paolo Bernardi*, Frank J. Schoenen*

Stop the pore: Prolonged Ca2+-dependent opening of the mitochondrial permeability transition pore (mtPTP) causes cell death. Herein we describe the discovery of novel small-molecule mtPTP inhibitors with picomolar activity in in vitro assays and high in vivo efficacy in a zebrafish model of muscular dystrophies.

ChemMedChem 2015, 10, No. 10, 1655–1671 [Full Paper]

Identification and Optimization of Anthranilic Acid Based Inhibitors of Replication Protein A

Identification and Optimization of Anthranilic Acid Based Inhibitors of Replication Protein A

James D. Patrone, Nicholas F. Pelz, Brittney S. Bates, Elaine M. Souza-Fagundes, Bhavatarini Vangamudi, Demarco V. Camper, Alexey G. Kuznetsov, Carrie F. Browning, Michael D. Feldkamp, Andreas O. Frank, Benjamin A. Gilston, Edward T. Olejniczak, Olivia W. Rossanese, Alex G. Waterson, Walter J. Chazin, Stephen W. Fesik*

Blocking recruitment: A high-throughput screening campaign and subsequent structure-guided optimization led to the identification of anthranilic acid based molecules that occupy the entire basic cleft of the 70 kDa subunit of replication protein A (RPA70N) and bind the protein with sub-micromolar affinity.

ChemMedChem 2016, 11, No. 8, 893–899 [Full Paper]

Discovery of Novel Allosteric Non-Bisphosphonate Inhibitors of Farnesyl Pyrophosphate Synthase by Integrated Lead Finding

Discovery of Novel Allosteric Non‐Bisphosphonate Inhibitors of Farnesyl Pyrophosphate Synthase by Integrated Lead Finding

Andreas L. Marzinzik*, René Amstutz, Guido Bold, Emmanuelle Bourgier, Simona Cotesta, J. Fraser Glickman, Marjo Götte, Christelle Henry, Sylvie Lehmann, J. Constanze D. Hartwieg, Silvio Ofner, Xavier Pellé, Thomas P. Roddy, Jean-Michel Rondeau, Frédéric Stauffer, Steven J. Stout, Armin Widmer, Johann Zimmermann, Thomas Zoller, Wolfgang Jahnke*

Beyond the bone: Farnesyl pyrophosphate synthase (FPPS) is an important target for osteoporosis and bone metastases, and holds promise for a number of non-bone diseases, including cancer, parasitic infections, progeria, and Alzheimer's disease. Herein we describe two novel chemotypes of allosteric FPPS inhibitors. These are useful leads to evaluate the therapeutic potential of FPPS inhibitors for these new indications.

ChemMedChem 2015, 10, No. 11, 1884–1891 [Full Paper]

Optimization of Inhibitors of Mycobacterium tuberculosis Pantothenate Synthetase Based on Group Efficiency Analysis

Optimization of Inhibitors of Mycobacterium tuberculosis Pantothenate Synthetase Based on Group Efficiency Analysis

Alvin W. Hung, H. Leonardo Silvestre, Shijun Wen, Guillaume P. C. George, Jennifer Boland, Tom L. Blundell, Alessio Ciulli, Chris Abell*

Dissecting potency: Group efficiency (GE) analysis is a powerful tool to examine the contribution of different groups within a compound towards protein binding. Here, GE analysis was used to examine the binding distribution of a lead molecule designed against Mycobacterium tuberculosis pantothenate synthetase. The substitution of the inefficient parts of the molecule led to the development of a more potent inhibitor.

ChemMedChem 2016, 11, No. 1, 38–42 [Communication]

Cancer Immunotherapy: Selected Targets and Small-Molecule Modulators

Cancer Immunotherapy: Selected Targets and Small‐Molecule Modulators

Hilmar Weinmann*

Small molecules for immuno-oncology: Cancer immunotherapy is currently generating a lot of excitement in the scientific community, as well as new hope for many cancer patients given some recent clinical successes. The discovery and development of new small-molecule modulators is a rapidly growing research area for medicinal chemists in immuno-oncology. This review provides a brief introduction into recent trends related to some selected targets and pathways for cancer immunotherapy and their small-molecule pharmacological modulators.

ChemMedChem 2016, 11, No. 5, 450–466 [Review]

Stimuli-Responsive Polymeric Nanoparticles for Nanomedicine

Stimuli‐Responsive Polymeric Nanoparticles for Nanomedicine

Carina I. C. Crucho*

Bringing life from cell death: Stimuli-responsive polymeric nanoparticles can respond to the microenvironment of a particular disease and its cells. Internal triggers as well as external devices permit temporally and spatially controlled drug delivery. The development of well-defined nanomedicines is critical for their behavior in vivo.

ChemMedChem 2015, 10, No. 1, 24–38 [Review]

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

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

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

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.

ChemMedChem 2015, 10, No. 1, 69–82 [Full Paper]

Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY 85-8501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases

Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY 85‐8501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases

Franz von Nussbaum*, Volkhart M.-J. Li*, Swen Allerheiligen, Sonja Anlauf, Lars Bärfacker, Martin Bechem, Martina Delbeck, Mary F. Fitzgerald, Michael Gerisch, Heike Gielen-Haertwig, Helmut Haning, Dagmar Karthaus, Dieter Lang, Klemens Lustig, Daniel Meibom, Joachim Mittendorf, Ulrich Rosentreter, Martina Schäfer, Stefan Schäfer, Jens Schamberger, Leila A. Telan, Adrian Tersteegen

Breathe better: It′s as potent as a low-molecular-weight inhibitor can get! Human neutrophil elastase (HNE) is a driver of pulmonary diseases. We describe the discovery of BAY 85-8501, a small-molecule inhibitor with picomolar in vitro potency against HNE. BAY 85-8501 is currently being assessed in clinical studies for pulmonary diseases.

ChemMedChem 2015, 10, No. 7, 1163–1173 [Full Paper]

Recent Book Reviews in 2016

Fragment-based Drug Discovery: Lessons and Outlook . Edited by Daniel A. Erlanson and Wolfgang Jahnke; Series Editors: Raimund Mannhold, Hugo Kubinyi, and Gerd Folkers

Fragment‐based Drug Discovery: Lessons and Outlook . Edited by Daniel A. Erlanson and Wolfgang Jahnke; Series Editors: Raimund Mannhold, Hugo Kubinyi, and Gerd Folkers

David Rees*

Wiley-VCH, Weinheim 2016. 528 pp., hardcover, €149.00.—ISBN  978-3-527-33775-0

ChemMedChem 10.1002/cmdc.201600256 [Book Review]

Drug Metabolism Prediction. Edited by Johannes Kirchmair

Drug Metabolism Prediction. Edited by Johannes Kirchmair

Lars Olsen*

Wiley-VCH, Weinheim 2014. 536 pp., hardcover, €149.00.—ISBN 978-3-527-33566-4

ChemMedChem 2016, 11, No. 1, 144–144 [Book Review]

In Silico Medicinal Chemistry: Computational Methods to Support Drug Design. Edited by Nathan Brown

In Silico Medicinal Chemistry: Computational Methods to Support Drug Design. Edited by Nathan Brown

Michel Petitjean, Anne-Claude Camproux*

ChemMedChem 2016, 11, No. 13, 1480–1481 [Book Review]

Privileged Scaffolds in Medicinal Chemistry. Design, Synthesis, Evaluation. Edited by Stefan Bräse

Privileged Scaffolds in Medicinal Chemistry. Design, Synthesis, Evaluation. Edited by Stefan Bräse

John Spencer*

RSC, Cambridge 2015. 476 pp., hardcover, £179.00.—ISBN  ISBN:978-1-78262-030-3

ChemMedChem 2016, 11, No. 10, 1107–1107 [Book Review]

Epigenetics for Drug Discovery. Edited by Nessa Carey

Epigenetics for Drug Discovery. Edited by Nessa Carey

Manfred Jung*

ChemMedChem 2016, 11, No. 6, 639–639 [Book Review]

See more book reviews.

Recent Special Issues

Drug Discovery for Autoimmune & Inflammatory Disorders
(Issue 02/2016, Guest Editor: Henning Steinhagen)

Protein-Protein Interactions
(Issue 08/2016, Guest Editors: Andrew J. Wilson and Patrick T. Gunning)

Polypharmacology & Multitarget Drugs
(Issue 12/2016, Guest Editors: Maria Laura Bolognesi and Andrea Cavalli)

See a list of all special issues.

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