Conference Reports
DOI: 10.1002/cmdc.201500208
Frontiers in Medicinal Chemistry 2015: Meet the Experts of MedChem near the Cradle of Medicinal and Pharmaceutical Chemistry Christof Wegscheid-Gerlach,*[a] Hans-Dieter Gerber,[b] and Wibke E. Diederich[b]
In the medieval town of Marburg, located in the heart of Germany, this year’s Joint German–Swiss Meeting Frontiers in Medicinal Chemistry (FiMC, March 15–18, 2015) was organized by the Divisions of Medicinal Chemistry of the Gesellschaft Deutscher Chemiker (GDCh), the Swiss Chemical Society (SCS), and the Division of Pharmaceutical/Medicinal Chemistry of the Deutsche Pharmazeutische Gesellschaft (DPhG). The conference took place at the University of Marburg, which is not only one of the oldest universities in Germany, but also happens to be the first university worldwide at which chemistry and pharmacy was taught. In 1609, the local duke, Moritz von HessenKassel, appointed Johannes Hartmann as a so-called “Professor of Chymiatrie”, a symbiosis of chemistry and pharmacy, in order to explore the potential of “chemistry” in supporting physicians to successfully practice medicine. Hence, pharmaceutical and medicinal chemistry has a long history at “Philipps-Universitt Marburg”, and today still hosts Germany’s largest school of pharmacy. Approximately 200 registered participants from all across Europe and overseas attended this international conference. Each scientific session included four to six lectures aimed at providing an overview of the following current topics: RNA therapeutics, CNS–neurodegeneration, anti-infectives and antivirals, highlights in technology and medicinal chemistry, as well as innovative novel drug releases. The schedule of the scientific program offered meeting participants abundant time and therefore excellent opportunities for networking among the sessions and during the social program. The meeting was inaugurated by welcome addresses given by Gerhard Klebe, chairman of the 2015 FiMC meeting, Ulrich Koert, vice president for research at the hosting university, and a representative of each organizing division (Eckard Ottow (GDCh), Stefan Laufer (DPhG), and Yves Auberson (SCS)). In the excellent opening lecture presented by Mike Hann (GSK, Stevenage, UK), the challenges accompanied by the discovery of effective and safe new drugs were illustrated. In particular, the lessons learned in the recent past and their implementa[a] Dr. C. Wegscheid-Gerlach+ Department of Pharmacy, Philipps-Universitt Marburg Wilhelm-Roser-Str. 2, 35032 Marburg (Germany) E-mail: [email protected] [b] H.-D. Gerber,+ Prof. Dr. W. E. Diederich+ Institute of Pharmaceutical Chemistry, Philipps-Universitt Marburg Marbacher Weg 6, 35032 Marburg (Germany) [+] These authors contributed equally to this work.
ChemMedChem 2015, 10, 1267 – 1271
tion in future medicinal chemistry projects to circumvent failures was addressed. The first day was wrapped up with a gettogether in combination with the first poster session, which, in a pleasant atmosphere, enabled fruitful discussions on the research results of the 55 submitted posters. Two additional poster sessions provided opportunities for further inspiring exchanges in the following days of the conference. RNA therapeutics On the second day, Jesper Wengel (University of Southern Denmark, Odense, Denmark) opened the session of RNA therapeutics, giving a concise overview of RNA as a drug target as well as on the newly emerging field of synthetic RNA mimics for the application as RNA-based drugs. The talk of Henrik Ørum (Roche Innovation Center, Copenhagen, Denmark) followed up on the previous contribution by focusing on the application of locked nucleic acids (LNA) as a new RNA-targeting drug class. The challenge of making drugs out of small interfering RNAs (siRNAs) was then addressed by Mutiah Manoharan (Alnylam Pharmaceuticals, Cambridge, USA), who illustrated the successful delivery of siRNAs by means of covalent conjugation to ligand-mediated uptake through a receptor expressed on the cells of interest. Arnold Grìnweller (PhilippsUniversitt, Marburg, Germany) presented a successful combination of RNA effectors with small-molecule inhibitors that influence miRNA regulation by PIM1 kinase. The final talk of this session, given by Jonathan Hall (ETH, Zìrich, Switzerland), once again highlighted the use of small drug-like ligands that target RNA. Overall, the RNA therapeutics session provided many insights into where medicinal chemistry expertise can contribute to further evolve this new drug target research field. CNS–neurodegeneration New concepts to cure neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and major depression are urgently needed, especially in light of today’s steadily ageing society. The focus of this session was thus laid on new target strategies and corresponding lead-finding campaigns. The lecture of Hans-Ulrich Demuth (Fraunhofer IZI, Halle (Saale), Germany) summarized the efforts to establish Glutaminyl Cyclases (QC) as new targets. Starting from the characterization of aminopeptidase-related enzymes and the discov-
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Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Conference Reports ery of new compounds for these, he also discussed the application of small-molecule QC inhibitors as well as passive immunization by employing antibodies. Oxidative stress induces neuronal cell death by mitochondrial impairment. Inhibition of Bcl-2 proteins may therefore provide effective neuroprotection. In this respect, David Andrews (University of Toronto, Toronto, Canada) introduced a liposome-based high-content screen for the detection of protein–protein inhibitors that interfere with the Bcl-2 proteins Bax and Bak, thereby preventing apoptosis. The talk of Carsten Culmsee (Philipps-Universitt, Marburg, Germany) pointed in the same direction by highlighting the key role of Bid, an additional member of the Bcl-2 family. On the one hand, his lecture dealt with the respective pharmacological approaches; on the other hand, first lead structures were shown. Finally, Felix Hausch (MPI of Psychiatry, Munich, Germany) presented selective inhibitors for the FK506-binding protein 51, which might serve as novel antidepressants.
Anti-infectives and antivirals The third day started off with Rolf Mìller (HIPS, Saarbrìcken, Germany), who highlighted the concept of using Streptomyces spp. bacteria as a source for identifying new lead structures for antibiotics against M. tuberculosis. Elucidation of the biosynthetic pathway of griselimycin enabled his research group to improve the ratio in favor of metabolically stable versus unstable griselimycin derivatives being produced in the bacteria. The lecture nicely acquainted the interplay of molecular biology and medicinal chemistry in identifying new antibiotic concepts. Cornelia Zumbrunn (Actelion Pharmaceuticals, Allschwill, Switzerland) addressed the challenge of overcoming resistance to antibiotics using a strategy to identify new compounds by combining pharmacophores of two well-known antibiotic classes. The principle aim of this concept was to obtain a novel mode of action to avoid cross-resistance with drugs in current use. In particular, the discovery of cadazolid and novel bacterial topoisomerase inhibitors (NBTI) lacking cross-resistance were illustrated. Ralf Bartenschlager (Ruprecht-Karls-Universitt, Heidelberg, Germany) described the development of a robust and easy-to-handle cell culture system for the identification of drug targets essential for the propagation of viruses such as hepatitis C. In his lecture, he presented a short overview of novel antiviral drugs that have been recently approved (see also the Innovative novel drug releases session below). The talk of Eva Altmann (Novartis, Basel, Switzerland) on the discovery of adenain inhibitors encompassed the optimization of this peptidomimetic compound class using a classical medicinal chemistry approach as well as structure-guided design strategies and the results of the respective biological evaluations. Various serine proteases can prevent influenza virus multicycle replication by inhibition of the surface hemagglutinin (HA). Eva Bçttcher-Friebertshuser (Philipps-Universitt, Marburg, Germany) gave insight into the results of the development of small-molecule inhibitors of the serine proteases furin, HAT, and TMPRSS2. Combining these new inhibitors with currently approved antivirals resulted in a strong synergistic ChemMedChem 2015, 10, 1267 – 1271
www.chemmedchem.org
effect, thus indicating that this could be a promising approach for the future development of prospective influenza drugs. Highlights in technology and medicinal chemistry In the field of drug residence time, Herbart Nar (Boehringer Ingelheim, Biberach, Germany) talked about the characterization of various DPP-4 inhibitors, focusing on enzyme kinetics, in vitro potency, and terminal half-life in the human body. The presentation of Robert Copeland (Epizyme Inc., Cambridge, USA) pointed in the same direction. Here, the benefit of deriving binding kinetics as an additional property for compound characterization was introduced. Gerhard Mìller (Merchachem, Nijmegen, Netherlands) commented on the importance of the design principle “escaping from flatland” using the latest chemoinformatics approaches. Privileged structures for GPCRs, protein kinases, and histone deacetylases with regard to residence times were introduced. Teresa Carlomagno (EMBL, Heidelberg, Germany) presented her INPHARMA-NMR data protocol as a rapid alternative for obtaining information on protein–ligand interactions. In particular, for targets that lack crystallographic information or for those that are too big to be studied by NMR, this is an invaluable technique that supports the generation of structure-based information for drug discovery projects. Nuska Tschammer (Friedrich-AlexanderUniversitt, Erlangen, Germany) was invited to give a lecture on the occasion of being awarded the Innovation Prize (Figure 1). She presented her latest results on the identification of the first potent biased negative and positive allosteric modulators of GPCRs. Within the scope of the international partnership of the DPhG and the Japanese Pharmaceutical Society (PSJ), Satoshi Shuto (Hokkaido University, Sapporo, Japan) participated at this year’s FiMC meeting as a representative of PSJ. He illustrated the development of potent ligands by using cyclopropane as starting point for a three-dimensional diversityoriented synthesis strategy to obtain conformationally restricted ligands for various targets.
Figure 1. Nuska Tschammer receives the Innovation Prize from Eckard Ottow, Head of the Division of Medicinal Chemistry of GDCh.
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Conference Reports Innovative novel drug releases Not only is the art of introducing new approaches for the discovery of new drugs an interesting topic for medicinal chemists, but so are illustrations of the development routes taken toward successfully approved drugs along with follow-up activities; all this was covered at the meeting. In this respect, Zhengying Pan (Peking University, Beijing, China) commenced the final day with his talk that demonstrated the impressive pharmacological Figure 3. The co-binding of an allosteric modulator to a receptor may enforce bias on the signaling of an orthoseffects of ibrutinib, which was teric ligand. As such, allosteric modulators may be advantageous in fine-tuning the response of the receptor very recently approved for use under specific conditions. Copyright Ó 2015, American Chemical Society; image adapted from Ref. [1] with permisin the EU and US. In addition, sion. the follow-up activities for the awardees for the 2015 Innovation Prize in recognition of their identification of novel irreversible BTK inhibitors were shown. joint efforts on investigating GPCR targets and inhibitors thereAstra Zeneca researchers discovered activated factor XI (FXIa) of: inhibitors by using a fragment-based approach. Ola Fjellstrçm Nuska Tschammer (Friedrich-Alexander-Universitt, Erlan(Astra Zeneca, Mçlndal, Sweden) outlined the concerted action gen, Germany) received the Innovation Prize for her research of virtual screening, NMR-based fragment screening, X-ray cryson the elucidation of the complex interactions between ortallography, and medicinal chemistry efforts to obtain selective thosteric ligands as well as allosteric modulators and GPCRs and orally bioavailable compounds. Nicholas A. Meanwell (Figure 2), based on synthesis and characterization of biased (Bristol-Meyers Squibb, Wallingford, USA) presented an optimisignaling (Figure 3) using site-directed mutagenesis, mass zation campaign of the prototypical HCV NS5A inhibitor daclaspectrometry, and functional assays. tasavir (approved for the market in 2014). The next steps reIn addition, Peter Kolb (Philipps-Universitt, Marburg, Gerquired for the identification of compounds with improved promany) was awarded for the development of computational apfiles toward resistant viruses was an additional aspect of his proaches for tailoring the selectivity of GPCR–ligand interactalk. Thomas Trieselmann (Boehringer Ingelheim, Biberach, tions (Figure 4). Facilitated by the availability of a multitude of Germany) closed this impressive diverse GPCR X-ray structures, structure-based computational session with his talk, which was methods can help to identify potent ligands with tailored sefocused on the discovery of cholectivity. Success stories of chemokine receptors (Figure 5) as lesteryl ester transfer protein (CETP) inhibitors starting from the identification of a development candidate to further follow-up CETP inhibitors based on exhaustive in vitro and in vivo characterizations. Prizes
Figure 2. Understanding the complex interactions between the orthosteric ligand and allosteric modulator and/or receptor are crucial for the development of therapeutics that target the chemokine system. Copyright Ó 2015, American Chemical Society; image reproduced from Ref. [1] with permission.
ChemMedChem 2015, 10, 1267 – 1271
The Innovation Prize acknowledges outstanding and innovative scientific achievements in the areas of medicinal and pharmaceutical chemistry. The Medicinal Chemistry Division of the GDCh and the Pharmaceutical/Medicinal Chemistry Division of the DPhG jointly award the Innovation Prize at each year’s FiMC meeting. This year, the committee selected two www.chemmedchem.org
Figure 4. Peter Kolb during his lecture on the occasion of being awarded with the Innovation Prize 2015.
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Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Conference Reports well as orexin receptor subtype 2 (Figure 6) were highlighted in his lecture. Since 2013, the respective divisions of GDCh and DPhG have sponsored three awards for outstanding PhD theses within the field of medicinal chemistry. Each awardee was invited to present their results in a short talk. For his thesis research, Johannes Schiebel (Julius-Maximilians-Universitt, Wìrzburg, Germany (now Philipps-Universitt, Marburg)) applied a combined crystallographic, kinetics, and computational approach for the comparison of two structurally related molecular scaf-
folds toward enoyl-acyl carrier protein reductase. The development of potent dengue virus protease inhibitors was the topic of the PhD thesis of Christoph Nitsche (Ruprechts-Karls Universitt, Heidelberg, Germany). The subject of the work of Dominik Thimm (Rheinische Friedrich-Wilhelms-Universitt, Bonn, Germany) was the de-orphanization of GPR35 by means of small molecules. He identified small molecular probes to elucidate the function of this receptor in the human body (Figure 7).
Figure 5. Comparison of selected docking poses for compound 2, a selective CXCR3 binder (a,b); compound 7, a dual binder (c,d); and compound 9, an exclusive CXCR4 binder (e,f) in the CXCR3 homology model (a,c,e) and the CXCR4 crystal structure (b,d,f). Bold numbers refer to the ligand identities in Ref. [1]. Ligands in the CXCR3 structure are shown in brick-red and in green in the CXCR4 structure. The proteins are shown in light grey. Residues are labeled whenever a ligand interacts with them. Roman numerals are used to label protein helices. Checks and crosses indicate that the respective receptor–ligand combination was predicted to be active or inactive, respectively. All predictions presented here were shown to be correct. Copyright Ó 2015, American Chemical Society; image reproduced from Ref. [1] with permission.
ChemMedChem 2015, 10, 1267 – 1271
www.chemmedchem.org
1270
Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Conference Reports Bìlow (Christian-Albrechts-Universitt Kiel, Germany), Anita Wegert (Merchachem, Nijmegen, Netherlands) and Lina Humbeck (Technische Universitt, Dortmund, Germany) summarized their presented works for the audience. Concluding remarks In addition to a number of excellent lectures given by internationally highly reputed researchers, the organizers also ensured that each session included one oral communication from a postdoctoral junior scientist. As mentioned above, the conference schedule provided sufficient time for the further scientific exchange. Coffee breaks, the conference dinner venue with an impressive view of Marburg castle, as well as the gettogether with draft beer and pretzels provided multiple opportunities for networking between all participants of the meeting, academic or industrial. A guided tour through the historic town center of Marburg or a tour of the “hands-on laboratory” at the CHEMIKUM Marburg completed the social program of the 2015 Frontiers in Medicinal Chemistry meeting.
Figure 6. Predicted binding mode of SB-674042, an OX2R agonist, in the OX2R X-ray structure. The protein is shown as a tan ribbon structure, and the agonist is shown in stick representation with green carbon atoms. The crystallographic binding mode of suvorexant is shown as a wire with tan carbons. Hydrogen bonds are indicated with yellow solid or dashed lines.
Frontiers in Medicinal Chemistry 2016 Interested scientists are cordially invited to participate at the next Joint German–French FiMC Meeting, which is scheduled to take place March 13–16, 2016 in the city of Bonn (Germany).
Acknowledgements
Figure 7. Johannes Schiebel, Dominic Thimm, and Christoph Nitsche (L to R) were awarded with the prize for outstanding PhD theses within the field of medicinal chemistry.
Finally, three ultra-short lectures given by the winners of the poster prizes were included in the scientific program. Julia von
ChemMedChem 2015, 10, 1267 – 1271
www.chemmedchem.org
The committee thanks Claudia Birkner (GDCh, Frankfurt) and Lydia Hartleben (Philipps-Universitt, Marburg) for their excellent work in preparing and organizing the meeting. Financial support of the German Research Foundation (DFG) is kindly acknowledged. The organizers also thank the following sponsors and financial donors: Abbvie, Actelion, Bayer, BioSolveIT, Boehringer Ingelheim, Merck Serono, Novartis and Roche (represented by Contact Group for Research Matters, Switzerland), and PhilippsApotheke Marburg. [1] D. Schmidt, V. Bernat, R. Brox, N. Tschammer, P. Kolb, ACS Chem. Biol. 2015, 10, 715 – 724.
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DOI: 10.1002/cmdc.201500208
Frontiers in Medicinal Chemistry 2015: Meet the Experts of MedChem near the Cradle of Medicinal and Pharmaceutical Chemistry Christof Wegscheid-Gerlach,*[a] Hans-Dieter Gerber,[b] and Wibke E. Diederich[b]
In the medieval town of Marburg, located in the heart of Germany, this year’s Joint German–Swiss Meeting Frontiers in Medicinal Chemistry (FiMC, March 15–18, 2015) was organized by the Divisions of Medicinal Chemistry of the Gesellschaft Deutscher Chemiker (GDCh), the Swiss Chemical Society (SCS), and the Division of Pharmaceutical/Medicinal Chemistry of the Deutsche Pharmazeutische Gesellschaft (DPhG). The conference took place at the University of Marburg, which is not only one of the oldest universities in Germany, but also happens to be the first university worldwide at which chemistry and pharmacy was taught. In 1609, the local duke, Moritz von HessenKassel, appointed Johannes Hartmann as a so-called “Professor of Chymiatrie”, a symbiosis of chemistry and pharmacy, in order to explore the potential of “chemistry” in supporting physicians to successfully practice medicine. Hence, pharmaceutical and medicinal chemistry has a long history at “Philipps-Universitt Marburg”, and today still hosts Germany’s largest school of pharmacy. Approximately 200 registered participants from all across Europe and overseas attended this international conference. Each scientific session included four to six lectures aimed at providing an overview of the following current topics: RNA therapeutics, CNS–neurodegeneration, anti-infectives and antivirals, highlights in technology and medicinal chemistry, as well as innovative novel drug releases. The schedule of the scientific program offered meeting participants abundant time and therefore excellent opportunities for networking among the sessions and during the social program. The meeting was inaugurated by welcome addresses given by Gerhard Klebe, chairman of the 2015 FiMC meeting, Ulrich Koert, vice president for research at the hosting university, and a representative of each organizing division (Eckard Ottow (GDCh), Stefan Laufer (DPhG), and Yves Auberson (SCS)). In the excellent opening lecture presented by Mike Hann (GSK, Stevenage, UK), the challenges accompanied by the discovery of effective and safe new drugs were illustrated. In particular, the lessons learned in the recent past and their implementa[a] Dr. C. Wegscheid-Gerlach+ Department of Pharmacy, Philipps-Universitt Marburg Wilhelm-Roser-Str. 2, 35032 Marburg (Germany) E-mail: [email protected] [b] H.-D. Gerber,+ Prof. Dr. W. E. Diederich+ Institute of Pharmaceutical Chemistry, Philipps-Universitt Marburg Marbacher Weg 6, 35032 Marburg (Germany) [+] These authors contributed equally to this work.
ChemMedChem 2015, 10, 1267 – 1271
tion in future medicinal chemistry projects to circumvent failures was addressed. The first day was wrapped up with a gettogether in combination with the first poster session, which, in a pleasant atmosphere, enabled fruitful discussions on the research results of the 55 submitted posters. Two additional poster sessions provided opportunities for further inspiring exchanges in the following days of the conference. RNA therapeutics On the second day, Jesper Wengel (University of Southern Denmark, Odense, Denmark) opened the session of RNA therapeutics, giving a concise overview of RNA as a drug target as well as on the newly emerging field of synthetic RNA mimics for the application as RNA-based drugs. The talk of Henrik Ørum (Roche Innovation Center, Copenhagen, Denmark) followed up on the previous contribution by focusing on the application of locked nucleic acids (LNA) as a new RNA-targeting drug class. The challenge of making drugs out of small interfering RNAs (siRNAs) was then addressed by Mutiah Manoharan (Alnylam Pharmaceuticals, Cambridge, USA), who illustrated the successful delivery of siRNAs by means of covalent conjugation to ligand-mediated uptake through a receptor expressed on the cells of interest. Arnold Grìnweller (PhilippsUniversitt, Marburg, Germany) presented a successful combination of RNA effectors with small-molecule inhibitors that influence miRNA regulation by PIM1 kinase. The final talk of this session, given by Jonathan Hall (ETH, Zìrich, Switzerland), once again highlighted the use of small drug-like ligands that target RNA. Overall, the RNA therapeutics session provided many insights into where medicinal chemistry expertise can contribute to further evolve this new drug target research field. CNS–neurodegeneration New concepts to cure neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and major depression are urgently needed, especially in light of today’s steadily ageing society. The focus of this session was thus laid on new target strategies and corresponding lead-finding campaigns. The lecture of Hans-Ulrich Demuth (Fraunhofer IZI, Halle (Saale), Germany) summarized the efforts to establish Glutaminyl Cyclases (QC) as new targets. Starting from the characterization of aminopeptidase-related enzymes and the discov-
1267
Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Conference Reports ery of new compounds for these, he also discussed the application of small-molecule QC inhibitors as well as passive immunization by employing antibodies. Oxidative stress induces neuronal cell death by mitochondrial impairment. Inhibition of Bcl-2 proteins may therefore provide effective neuroprotection. In this respect, David Andrews (University of Toronto, Toronto, Canada) introduced a liposome-based high-content screen for the detection of protein–protein inhibitors that interfere with the Bcl-2 proteins Bax and Bak, thereby preventing apoptosis. The talk of Carsten Culmsee (Philipps-Universitt, Marburg, Germany) pointed in the same direction by highlighting the key role of Bid, an additional member of the Bcl-2 family. On the one hand, his lecture dealt with the respective pharmacological approaches; on the other hand, first lead structures were shown. Finally, Felix Hausch (MPI of Psychiatry, Munich, Germany) presented selective inhibitors for the FK506-binding protein 51, which might serve as novel antidepressants.
Anti-infectives and antivirals The third day started off with Rolf Mìller (HIPS, Saarbrìcken, Germany), who highlighted the concept of using Streptomyces spp. bacteria as a source for identifying new lead structures for antibiotics against M. tuberculosis. Elucidation of the biosynthetic pathway of griselimycin enabled his research group to improve the ratio in favor of metabolically stable versus unstable griselimycin derivatives being produced in the bacteria. The lecture nicely acquainted the interplay of molecular biology and medicinal chemistry in identifying new antibiotic concepts. Cornelia Zumbrunn (Actelion Pharmaceuticals, Allschwill, Switzerland) addressed the challenge of overcoming resistance to antibiotics using a strategy to identify new compounds by combining pharmacophores of two well-known antibiotic classes. The principle aim of this concept was to obtain a novel mode of action to avoid cross-resistance with drugs in current use. In particular, the discovery of cadazolid and novel bacterial topoisomerase inhibitors (NBTI) lacking cross-resistance were illustrated. Ralf Bartenschlager (Ruprecht-Karls-Universitt, Heidelberg, Germany) described the development of a robust and easy-to-handle cell culture system for the identification of drug targets essential for the propagation of viruses such as hepatitis C. In his lecture, he presented a short overview of novel antiviral drugs that have been recently approved (see also the Innovative novel drug releases session below). The talk of Eva Altmann (Novartis, Basel, Switzerland) on the discovery of adenain inhibitors encompassed the optimization of this peptidomimetic compound class using a classical medicinal chemistry approach as well as structure-guided design strategies and the results of the respective biological evaluations. Various serine proteases can prevent influenza virus multicycle replication by inhibition of the surface hemagglutinin (HA). Eva Bçttcher-Friebertshuser (Philipps-Universitt, Marburg, Germany) gave insight into the results of the development of small-molecule inhibitors of the serine proteases furin, HAT, and TMPRSS2. Combining these new inhibitors with currently approved antivirals resulted in a strong synergistic ChemMedChem 2015, 10, 1267 – 1271
www.chemmedchem.org
effect, thus indicating that this could be a promising approach for the future development of prospective influenza drugs. Highlights in technology and medicinal chemistry In the field of drug residence time, Herbart Nar (Boehringer Ingelheim, Biberach, Germany) talked about the characterization of various DPP-4 inhibitors, focusing on enzyme kinetics, in vitro potency, and terminal half-life in the human body. The presentation of Robert Copeland (Epizyme Inc., Cambridge, USA) pointed in the same direction. Here, the benefit of deriving binding kinetics as an additional property for compound characterization was introduced. Gerhard Mìller (Merchachem, Nijmegen, Netherlands) commented on the importance of the design principle “escaping from flatland” using the latest chemoinformatics approaches. Privileged structures for GPCRs, protein kinases, and histone deacetylases with regard to residence times were introduced. Teresa Carlomagno (EMBL, Heidelberg, Germany) presented her INPHARMA-NMR data protocol as a rapid alternative for obtaining information on protein–ligand interactions. In particular, for targets that lack crystallographic information or for those that are too big to be studied by NMR, this is an invaluable technique that supports the generation of structure-based information for drug discovery projects. Nuska Tschammer (Friedrich-AlexanderUniversitt, Erlangen, Germany) was invited to give a lecture on the occasion of being awarded the Innovation Prize (Figure 1). She presented her latest results on the identification of the first potent biased negative and positive allosteric modulators of GPCRs. Within the scope of the international partnership of the DPhG and the Japanese Pharmaceutical Society (PSJ), Satoshi Shuto (Hokkaido University, Sapporo, Japan) participated at this year’s FiMC meeting as a representative of PSJ. He illustrated the development of potent ligands by using cyclopropane as starting point for a three-dimensional diversityoriented synthesis strategy to obtain conformationally restricted ligands for various targets.
Figure 1. Nuska Tschammer receives the Innovation Prize from Eckard Ottow, Head of the Division of Medicinal Chemistry of GDCh.
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Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Conference Reports Innovative novel drug releases Not only is the art of introducing new approaches for the discovery of new drugs an interesting topic for medicinal chemists, but so are illustrations of the development routes taken toward successfully approved drugs along with follow-up activities; all this was covered at the meeting. In this respect, Zhengying Pan (Peking University, Beijing, China) commenced the final day with his talk that demonstrated the impressive pharmacological Figure 3. The co-binding of an allosteric modulator to a receptor may enforce bias on the signaling of an orthoseffects of ibrutinib, which was teric ligand. As such, allosteric modulators may be advantageous in fine-tuning the response of the receptor very recently approved for use under specific conditions. Copyright Ó 2015, American Chemical Society; image adapted from Ref. [1] with permisin the EU and US. In addition, sion. the follow-up activities for the awardees for the 2015 Innovation Prize in recognition of their identification of novel irreversible BTK inhibitors were shown. joint efforts on investigating GPCR targets and inhibitors thereAstra Zeneca researchers discovered activated factor XI (FXIa) of: inhibitors by using a fragment-based approach. Ola Fjellstrçm Nuska Tschammer (Friedrich-Alexander-Universitt, Erlan(Astra Zeneca, Mçlndal, Sweden) outlined the concerted action gen, Germany) received the Innovation Prize for her research of virtual screening, NMR-based fragment screening, X-ray cryson the elucidation of the complex interactions between ortallography, and medicinal chemistry efforts to obtain selective thosteric ligands as well as allosteric modulators and GPCRs and orally bioavailable compounds. Nicholas A. Meanwell (Figure 2), based on synthesis and characterization of biased (Bristol-Meyers Squibb, Wallingford, USA) presented an optimisignaling (Figure 3) using site-directed mutagenesis, mass zation campaign of the prototypical HCV NS5A inhibitor daclaspectrometry, and functional assays. tasavir (approved for the market in 2014). The next steps reIn addition, Peter Kolb (Philipps-Universitt, Marburg, Gerquired for the identification of compounds with improved promany) was awarded for the development of computational apfiles toward resistant viruses was an additional aspect of his proaches for tailoring the selectivity of GPCR–ligand interactalk. Thomas Trieselmann (Boehringer Ingelheim, Biberach, tions (Figure 4). Facilitated by the availability of a multitude of Germany) closed this impressive diverse GPCR X-ray structures, structure-based computational session with his talk, which was methods can help to identify potent ligands with tailored sefocused on the discovery of cholectivity. Success stories of chemokine receptors (Figure 5) as lesteryl ester transfer protein (CETP) inhibitors starting from the identification of a development candidate to further follow-up CETP inhibitors based on exhaustive in vitro and in vivo characterizations. Prizes
Figure 2. Understanding the complex interactions between the orthosteric ligand and allosteric modulator and/or receptor are crucial for the development of therapeutics that target the chemokine system. Copyright Ó 2015, American Chemical Society; image reproduced from Ref. [1] with permission.
ChemMedChem 2015, 10, 1267 – 1271
The Innovation Prize acknowledges outstanding and innovative scientific achievements in the areas of medicinal and pharmaceutical chemistry. The Medicinal Chemistry Division of the GDCh and the Pharmaceutical/Medicinal Chemistry Division of the DPhG jointly award the Innovation Prize at each year’s FiMC meeting. This year, the committee selected two www.chemmedchem.org
Figure 4. Peter Kolb during his lecture on the occasion of being awarded with the Innovation Prize 2015.
1269
Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Conference Reports well as orexin receptor subtype 2 (Figure 6) were highlighted in his lecture. Since 2013, the respective divisions of GDCh and DPhG have sponsored three awards for outstanding PhD theses within the field of medicinal chemistry. Each awardee was invited to present their results in a short talk. For his thesis research, Johannes Schiebel (Julius-Maximilians-Universitt, Wìrzburg, Germany (now Philipps-Universitt, Marburg)) applied a combined crystallographic, kinetics, and computational approach for the comparison of two structurally related molecular scaf-
folds toward enoyl-acyl carrier protein reductase. The development of potent dengue virus protease inhibitors was the topic of the PhD thesis of Christoph Nitsche (Ruprechts-Karls Universitt, Heidelberg, Germany). The subject of the work of Dominik Thimm (Rheinische Friedrich-Wilhelms-Universitt, Bonn, Germany) was the de-orphanization of GPR35 by means of small molecules. He identified small molecular probes to elucidate the function of this receptor in the human body (Figure 7).
Figure 5. Comparison of selected docking poses for compound 2, a selective CXCR3 binder (a,b); compound 7, a dual binder (c,d); and compound 9, an exclusive CXCR4 binder (e,f) in the CXCR3 homology model (a,c,e) and the CXCR4 crystal structure (b,d,f). Bold numbers refer to the ligand identities in Ref. [1]. Ligands in the CXCR3 structure are shown in brick-red and in green in the CXCR4 structure. The proteins are shown in light grey. Residues are labeled whenever a ligand interacts with them. Roman numerals are used to label protein helices. Checks and crosses indicate that the respective receptor–ligand combination was predicted to be active or inactive, respectively. All predictions presented here were shown to be correct. Copyright Ó 2015, American Chemical Society; image reproduced from Ref. [1] with permission.
ChemMedChem 2015, 10, 1267 – 1271
www.chemmedchem.org
1270
Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Conference Reports Bìlow (Christian-Albrechts-Universitt Kiel, Germany), Anita Wegert (Merchachem, Nijmegen, Netherlands) and Lina Humbeck (Technische Universitt, Dortmund, Germany) summarized their presented works for the audience. Concluding remarks In addition to a number of excellent lectures given by internationally highly reputed researchers, the organizers also ensured that each session included one oral communication from a postdoctoral junior scientist. As mentioned above, the conference schedule provided sufficient time for the further scientific exchange. Coffee breaks, the conference dinner venue with an impressive view of Marburg castle, as well as the gettogether with draft beer and pretzels provided multiple opportunities for networking between all participants of the meeting, academic or industrial. A guided tour through the historic town center of Marburg or a tour of the “hands-on laboratory” at the CHEMIKUM Marburg completed the social program of the 2015 Frontiers in Medicinal Chemistry meeting.
Figure 6. Predicted binding mode of SB-674042, an OX2R agonist, in the OX2R X-ray structure. The protein is shown as a tan ribbon structure, and the agonist is shown in stick representation with green carbon atoms. The crystallographic binding mode of suvorexant is shown as a wire with tan carbons. Hydrogen bonds are indicated with yellow solid or dashed lines.
Frontiers in Medicinal Chemistry 2016 Interested scientists are cordially invited to participate at the next Joint German–French FiMC Meeting, which is scheduled to take place March 13–16, 2016 in the city of Bonn (Germany).
Acknowledgements
Figure 7. Johannes Schiebel, Dominic Thimm, and Christoph Nitsche (L to R) were awarded with the prize for outstanding PhD theses within the field of medicinal chemistry.
Finally, three ultra-short lectures given by the winners of the poster prizes were included in the scientific program. Julia von
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The committee thanks Claudia Birkner (GDCh, Frankfurt) and Lydia Hartleben (Philipps-Universitt, Marburg) for their excellent work in preparing and organizing the meeting. Financial support of the German Research Foundation (DFG) is kindly acknowledged. The organizers also thank the following sponsors and financial donors: Abbvie, Actelion, Bayer, BioSolveIT, Boehringer Ingelheim, Merck Serono, Novartis and Roche (represented by Contact Group for Research Matters, Switzerland), and PhilippsApotheke Marburg. [1] D. Schmidt, V. Bernat, R. Brox, N. Tschammer, P. Kolb, ACS Chem. Biol. 2015, 10, 715 – 724.
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