BOOK OF ABSTRACTS BOOK OF ABSTRACTS 2016 Organised by: On behalf of: EFMC-ISMC 2016 tel. office: +32 10 45 47 77 All information in this Manchester, UK, 2016 SYMPOSIUM SECRETARIAT tel. onsite in Manchester: +32 495 240864 programme book is accurate LD Organisation s.p.r.l. mail: [email protected] at the time of printing August 28-September 1 Scientific Conference Producers website: www.efmc-ismc.org Rue Michel de Ghelderode 33/2 www.efmc-ismc.org 1348 Louvain-la-Neuve, Belgium TABLE OF CONTENT Plenary Lectures 3 Award & Prize Lectures 11 Invited Lectures & Oral Communications 19 Posters 121 Drug Discovery Approaches Toward Targeting Ras 121 New Antibacterials. An Update 123 Peptides: Pushing Permeability and Bioavailability Beyond the Rule of 5 139 Molecular Tissue Targeting 143 First Time Disclosures 147 Making Small Molecule Synthesis Simpler, General, and Automatic 153 Hot Topics in Cardiovascular Diseases Research 163 Neglected Diseases 171 Synthesis Driven Innovation 195 Modulation of Protein-Protein Interactions - Novel Opportunities for Drug Discovery 213 Current Advances and Future Opportunities for the Treatment of Neurodegenerative Disorders 225 Big Data in Medicinal Chemistry 243 New Horizons in GPCR-targeted Medicinal Chemistry 249 Novel Approaches to the Treatment of Cancer 263 Emerging Topics 295 Innovation in Kinase Drug Discovery 305 The Importance of Solute Carrier Transporters in Drug Discovery 319 Covalent Drugs Revisited 323 Novel Molecular Probes for in Vivo Chemistry 327 Recent Advances on Approaches to Treat Pain 331 High Throughput Screening Strategies to Obtain High Quality Leads 335 Late Breaking News 343 Showcase Brazil 347 Other 349 Index of Abstracts 377 Index of Authors 407 1 NOTES 2 PLENARY LECTURES 3 PL001 SCIENCE, ART AND DRUG DISCOVERY, A PERSONAL PERSPECTIVE Simon Campbell CBE FRS Former SVP for WW Discovery at Pfizer [email protected] At the start of our research programme that lead to amlodipine, a once-daily calcium antagonist for the treatment of angina and hypertension, there were over 90 published patents around the parent dihydropyridine ring system which posed a significant challenge for innovative drug design. Moreover, all agents of the class suffered poor pharmacokinetics, and there was little information on how these might be improved. However, rational medicinal chemistry led to a novel series of dihydropyridines with potent calcium antagonist activity which displayed high, and uniform bioavailability, together with long plasma half-lives. After extensive pharmacological profiling, UK 48,340 (amlodipine) was selected for clinical development and subsequently received worldwide approval as Norvascä for the treatment of hypertension and angina. Norvascä became the world’s leading antihypertensive agent and the fourth best selling drug, with some billions of patient days of therapy achieved since launch Sildenafil, the first oral treatment for male erectile dysfunction, was the result of a cardiovascular research programme to block the action of PDE 5 and increase tissue levels of cGMP, even though the endogenous ligand that stimulated guanylate cyclase was unknown at the time. Starting from zaprinast, a weak and non-selective PDE 5 inhibitor, computer modelling guided rational medicinal chemistry to achieve significant increases in potency and selectivity within a novel series of pyrazolopyrimidones. Optimisation of SARs and pharmacokinetics led to UK 92,480 (sildenafil) that was essentially devoid of cardiovascular activity in clinical trials. However, the emerging role of nitric oxide and cGMP in controlling blood flow in the penis suggested that sildenafil would have a beneficial effect on erectile dysfunction. This hypothesis was confirmed by extensive clinical trials in nearly 5,000 patients and sildenafil was approved as Viagraä for the treatment of male erectile dysfunction. Viagraä became one of the most widely prescribed medicines, and has been used by 100s of millions of patients throughout the World. These research programmes will be discussed from a personal perspective that will highlight the importance of multidisciplinary project teams, challenges that arose during discovery and development, and factors that influenced key decisions. 4 PL002 THE EUROPEAN RESEARCH COUNCIL (ERC) AND ITS SUPPORT FOR MEDICINAL CHEMISTRY Klaus Bock University of Copenhagen Set up in 2007 by the European Union, the fundamental activity of the European Research Council (ERC) is to provide attractive, long-term funding to support excellent investigators and their research teams to pursue ground-breaking, high-gain/ high-risk research. Supporting best researchers in any field of research on the sole criterion of excellence is expected to have a direct impact through advances at the frontier of knowledge, opening the way to creating new scientific and technological results, which ultimately can lead to innovation. The ERC uses a typical panel-based peer-review system, in which panels of high-level scientists and/or scholars make recommendations for funding. The ERC panel structure consists of 25 panels across three domains: Social sciences and Humanities (SH), Life sciences (LS), Physical and Engineering Sciences (PE). At ERC chemical research is funded mainly in two big panels: PE4 “Physical and Analytical Chemical Sciences” and PE5 “Synthetic Chemistry and Materials”. Around 580 Starting, Consolidator and Advanced grants were awarded between 2007 and 2015 in these two panels with a total value of 1 billion euro (or almost 10% of the entire ERC budget awarded to the three main types of grants in this period). About 1 in 6 grants in panels PE4 and PE5 are working on medicinal chemistry or perform research with impact in medicine and on medical applications (including drugs). The areas where ERC grantees are most active are: - the creation of new molecular entities and subsequent exploitation of their properties for drug design and synthesis. The problems and difficulties associated with chemical syntheses (e.g. more rapid and robust techniques in organic synthesis) are addressed in many of these grants. A few projects are in the area of bioinorganic chemistry and explore new therapeutic applications of metal complexes. Other projects tend to focus on mechanistic studies of biochemical processes and reactions, on proteomics and on new approaches in drug design and delivery. Projects dealing with drug design cover a broad spectrum of research questions, ranging from development and analysis of new drugs and their impact on specific diseases (cancer, Alzheimer's disease, HIV, etc.) to the development of improved methods for drug analysis (more selective and efficient screening methods, enhancing the existing libraries of spectra of compounds, etc.); - research for improved diagnosis, early diagnosis and prognosis for preventive and personalized medicine; - design and preparation of new materials that interact with components of living systems in view of therapeutic or diagnostic applications. Materials targeted by these projects are, for example, hydrogels with applications in tissue engineering and repair, optical metamaterials, supramolecular biomaterials etc. Nanoscale engineering is a promising road for the development of novel materials with tailor-made properties, achieved by precise control of the materials structure and composition; - development of advanced imaging techniques (e.g. magnetic resonance, surgical imaging) or spectroscopic methods used in medicine. Projects doing research in medicinal chemistry are found in other ERC panels as well, especially in some of the LS panels and, to a lesser degree, in the engineering panels (PE7 “Systems and communication engineering” and PE8 “Products and process engineering”). My presentation will offer more details on the scope and objectives of ERC projects in medicinal chemistry as well as information about their results. 5 PL003 LATE-STAGE FLUORINATION Tobias Ritter (1,2,3) 1) Max-Planck-Institut fuer Kohlenforschung Kaiser-Wilhelm-Platz 1, 45470 Muelheim Germany 2) Harvard University Department of Chemistry and Chemical Biology 12 Oxford Street, Cambridge, MA 02138 USA 3) Massachusetts General Hospital Department of Radiology 55 Fruit Street, Boston, MA 02129 USA The unnatural isotope fluorine–18 (18F) is used as a positron emitter in molecular imaging. Currently, many potentially useful 18F-labeled probe molecules are inaccessible for imaging, because no fluorination chemistry is available to make them. Syntheses must be rapid on account of the 110-minute half-life of 18F and benefit from using [18F]fluoride due to practical access and suitable isotope enrichment. But [18F]fluoride chemistry has been limited in reaction and substrate scope. I will describe the development of novel, modern fluorination reactions and evaluate them based on their utility for F-19 and F-18 chemistry. Late-stage fluorination enables the synthesis of new drug candidates and conventionally unavailable positron emission tomography (PET) tracers for anticipated applications in pharmaceutical development as well as pre-clinical and clinical PET imaging. References 1) T. Furuya, A. S. Kamlet, T. Ritter “Catalysis for Fluorination and Trifluoromethylation” Nature, 2011, 473, 470. 2) E. Lee, A. S. Kamlet, D. C. Powers, C. N. Neumann, G. B. Boursalian, T. Furuya, D. C. Choi, J. M. Hooker, T. Ritter “A fluoride-derived electrophilic late-stage fluorination reagent for PET imaging” Science 2011, 334, 639. 3) C. N. Neumann, J. M. Hooker, T. Ritter