EFMC ASMC 2017 – Results from our collaboration with Merck

EDELRIS had the opportunity in August 2017 to present the work carried out in collaboration with Merck. This collaboration is a perfect example of the relevance and complementarity of EDELRIS’ Services.

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The Annual Meeting 2017 American Association for Cancer Research

Our partner Bayer HealthCare presented interesting results from a collaboration with EDELRIS at the Annual Meeting AARC in Washington.
This study case concerns a service of hit to lead on an epigenetic regulator: ATAD2. The work carried out by EDELRIS EDELRIS improved the affinity, selectivity and diffusion in tissues from Hits initially identified from a DNA-encoded compound libraries.

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An expedient synthesis of non-racemic N-alkylated pyrrolidin-2,5-diones and piperidin-2,6-diones as peptidomimetics

In our hands, access to 2 novel peptidomimetic scaffolds, based on N-alkylated pyrrolidin-2,5-diones and piperidin-2,6-diones (1), proved to be much more challenging than anticipated. In this short communication, we disclose the strategies that we explored and our final route choices to the desired scaffolds with control of both stereocenters.

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A metal-catalyzed enyne-cyclization step for the synthesis of bi- and tricyclic scaffolds amenable to molecular library production

A facile metal-catalyzed diversification step for the synthesis of novel bi- and tricyclic scaffolds from enyne substrates is reported in this study. From a single starting material, topologically diverse scaffolds for library synthesis can be generated and decorated in a few steps. The methodology was used to produce a library of 490 compounds within the European Lead Factory (ELF) Consortium.

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SAHOC2016: [5+2]-Cycloaddition reactions for the generation of diverse 3D-scaffolds and library synthesis

Cycloaddition reactions are highly useful tools to address 3D-rich and functionalized scaffolds. This presentation will show the successful applications of [5+2]-cycloaddition reactions to access library scaffolds containing seven-membered rings. The chemistries were validated by the University of Leeds scientists and after transfer of knowledge to our scientists at EDELRIS, up-scaling and final library syntheses were effectively performed. Hurdles, solutions and outcomes will be discussed.

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Unprecedented inhibitors of the ATAD2 bromodomain from a DNA-encoded chemical library screen

On the occasion of the 5th International Symposium on DNA-encoded chemical libraries (Zürich, August 26, 2016), Bayer AG discloses a poster co-authored by X-Chem and Edelris, and describing the discovery of BAY-850, a selective ATAD2 small molecule inhibitor, underscoring the value of DNA-encoded chemical libraries to address difficult-to-drug targets (soon to be published).

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[3+2]-Cycloaddition reaction: Synthesis of Libraries of Drug-Like pyrrolidine scaffolds

The [3+2]-cycloaddition reaction is a powerful tool to address 3D-rich and highly functionalized scaffolds for chemical library development. Applying this methodology, two diverse pyrrolidine containing scaffolds were designed. The in situ generated nitrone was reacted with N-Boc 2,5-dihydro-1H-pyrrole and its analog. The obtained isoxazolidine cycloaddition adducts were reduced and functionalized, leading to multiple entry points for diversity generation. Two 500-compound libraries were synthesized, validating the concept.

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Tandem Mannich/Diels–Alder reactions for the synthesis of indole compound libraries

tandem Mannich/Diels–Alder sequence is demonstrated in this studies for the synthesis of an O-bridged octahydro -isoindole core bearing an indole moiety. This scaffold displays a high Fsp 3 value, several chiral centers and a 500-compound library is being produced within the European Lead Factory Consortium.

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Scaffold Hopping from Complex 3D Fragments

There is a strong interest for the discovery of novel inhibitors of Caspase-1 (ICE), a protein involved in various inflammatory diseases such as rheumatoid arthritis, osteoarthritis or psoriasis. In order to develop new inhibitors, we used our EDEN platform (Edelris Discovery ENgine) to successfully explore the possibility to rescaffold competitor's ligands from innovative, 3D-enriched Keymical FragmentsTM.

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Expansion of chemical space for collaborative lead generation and drug discovery: the European Lead Factory Perspective

The European Lead Factory (ELF) project is addressing the challenge of generation and maintenance of a competitive compound collection by leveraging the diverse experience and know-how of academic groups and small and medium enterprises (SMEs) engaged in synthetic and/or medicinal chemistry. Here, we describe the novelty, diversity, structural complexity, physicochemical characteristics and overall attractiveness of the first batch of 50.000 ELF compounds for HTS purposes.

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Exploitation of the Ugi–Joullié Reaction in the Synthesis of Libraries of Drug-Like Bicyclic Hydantoins

A general and efficient method for the synthesis of drug-like fused bicyclic hydantoins is reported. An Ugi–Joullié reaction/cyclisation sequence was exploited as the key complexity-generating process, which enabled the synthesis of large small molecule libraries, leading to the production of >1000 compounds for addition to the screening collection of the European Lead Factory.

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Synthesis of (Arylamido)pyrrolidinone Libraries through Ritter-Type Cascade Reactions of Dihydroxylactams

The Ritter-type reaction of arylnitriles and N-acyliminium ions generated in situ from dihydroxy-g-lactams gave tetrahydropyrrolo[2,3-d]oxazol-5-ones in excellent yields and with high diastereoselectivity. Subsequent acidic hydrolysis yielded new (arylamido)pyrrolidinones. A combined one-step Ritter–hydrolysis procedure proved to be of equal efficiency. Within the European Lead Factory Consortium, this versatile method was successfully used for the production of a drug-like molecular library (+500 compounds) for biological screening.

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WO2015036442: Methods and pharmaceutical compositions for the treatment of Hepatitis B virus infection

Hepatitis B is still a major public health problem with more than 350 million people chronically infected worldwide, 20 to 40% of them being at risk of developing chronic liver disease, cirrhosis and hepatocellular carcinoma. Despite the existence of an effective preventive vaccine, the hepatitis B virus infection is still rampant in many countries, even developed ones, with an estimated 4.5 million cases of infection per year worldwide. Edelris and its partners Inserm and Poxel have identified FXR as a therapeutic target for HBV and discovered new compounds leading to a strong inhibition of viral DNA and viral antigen production.

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WO2015028095A1: Derivatives of macrocyclic natural product Branimycin (and their use for the treatment of bacterial infectious diseases)

Contribution from Edelris: The invention patented by Galapagos NV relates to novel Branimycin derivatives with formula (I) that are useful in the treatment of infectious diseases, in particular those causing significant morbidity in human. These compounds are active against a specific enzyme in the bacterial DNA replicative process. Edelris was more specifically involved in the synthesis, purification and structural characterization of these novel derivatives.

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Innovative approaches to the design and synthesis of small molecule libraries

This editorial by Pr. Nelson (Leeds University) and Dr. Roche (Edelris) is dedicated to innovative approaches to the design and synthesis of small molecular libraries.

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Aminomethylhydroxylation of alkenes: Exploitation in the synthesis of scaffolds for small molecule libraries

The application of [4+2] cycloadditions between alkenes and an N-benzoyl iminium species, generated in situ under acidic conditions, is described in the synthesis of diverse molecular scaffolds. The key reaction led to the formation of cyclic imidates in good yield and with high regioselectivity. It was demonstrated that the cyclic imidates may be readily converted into 1,3-amino alcohols. Incorporation of orthogonally-reactive functionality, such as aryl and alkyl bromides, into the cycloaddition substrates enabled the synthesis of additional scaffolds.

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Synthesis of 1,4,5 trisubstituted γ-lactams via a 3-component cascade reaction

A three component one-pot cascade reaction was developed for the synthesis of 1,4,5-trisubstituted γ-lactams. The resulting scaffold can be modified independently at three positions, two of which are conveniently accessed by changing the components of the one-pot reaction. The phases of building block generation, scaffold synthesis and subsequent appendage modification were adapted to library production, which resulted in a screening library of 500 compounds.

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Design, synthesis and decoration of molecular scaffolds for exploitation in the production of alkaloid-like libraries

The design, synthesis and decoration of six small molecule libraries is described. Each library was inspired by structures embedded in the framework of specific alkaloid natural products. The development of optimised syntheses of the required molecular scaffolds is described, in which reactions including Pd-catalysed aminoarylation and dipolar cycloadditions have been exploited as key steps. In total, the research has led to the successful synthesis of >2500 novel alkaloid-like compounds for addition to the screening collection (the Joint European Compound Library, JECL) of the European Lead Factory.

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Synthesis of non racemic 2,5-pyrrolidinedione and 2,6-piperidinedione peptidomimetics

The synthesis of conformationnally restricted peptidomimetics through cyclisation is of interest in the drug development process. The preparation of imide by cyclisation of aspartic or glutamic carboxylic acid side chain with backbone amide is scarcely described (pathway a). Moreover, the C-N bond formation on amino succinimide or aminoglutarimide derivatives has never been reported to our knowledge (pathway b). This poster presented at the BOSS 2014 outlines the different strategies devised and applied to overcome selectivity and epimerisation issues in the synthesis of aminosuccinimide and aminoglutarimide containing peptides.

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Pd-catalyzed carboamination: a key reaction to explore 3D diversity

The palladium-catalyzed carboamination of N-protected γ-aminoalkenes with aryl bromides is a powerful reaction to access functionalized pyrrolidines with high levels of diastereoselectivity. The poster presents the synthesis of two pyrrolidine-based libraries, illustrating our process in the development and production phases. Hurdles, solutions and outcomes are discussed.

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The metabolic sensors FXRα, PGC-1α, and SIRT1 cooperatively regulate hepatitis B virus transcription

Hepatitis B virus (HBV) genome transcription is highly dependent on liver-enriched, metabolic nuclear receptors (NRs). Among others, NR farnesoid X receptor α (FXRα) enhances HBV core promoter activity and pregenomic RNA synthesis. Interestingly, two food-withdrawal-induced FXRα modulators, peroxisome proliferator-activated receptor-ɣ coactivator 1α (PGC-1α) and deacetylase SIRT1, have been found to be associated with HBV genomes ex vivo. Whereas PGC-1α induction was shown to increase HBV replication, the effect of SIRT1 on HBV transcription remains unknown. Here, we showed that, in hepatocarcinoma- derived Huh-7 cells, combined activation of FXRα by GW4064 and SIRT1 by activator 3 increased HBV core promoter-controlled luciferase expression by 25-fold, compared with a 10-fold increase with GW4064 alone.

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Rhodium(III)-catalyzed allylic C–H bond amination. Synthesis of cyclic amines from ω-unsaturated N-sulfonylamines

For the first time, intramolecular allylic amination was conducted using rhodium(III) according to an “inner-sphere” type mechanism with amines activated by only one electron-withdrawing group. The activation of C(sp3)–H bonds was chemoselective and allows the access to a variety of substituted cyclic amines such as pyrrolidines and piperidines.

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(E)-Dimethyl 2-Oxopent-3-enylphosphonate: An Excellent Substrate for Cross- Metathesis – Easy Access to Functionalized Heterocycles

Simple and efficient access to tetrahydrofurans, tetrahydropyrans, and pyrrolidines through a tandem cross-metathesis/1,4-addition process from (E)-dimethyl 2-oxopent-3-enylphosphonate and N-protected unsaturated amines or alcohols under microwave irradiation is described. As the Grubbs–Hoveyda catalyst is highly chemoselective, a diversity of functionalized heterocycles were synthesized. Furthermore, an additional functionalization can be performed due to the presence of a side chain that possesses a ketophosphonate at the C2 position of the heterocycle.

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N-Formylsaccharin: A New Formylating Agent

N-Formylsaccharin has been revealed to be an efficient and chemoselective formylating agent of amines.The latter is a solid, is very cheap, easy to handle, stable, it can react under mild reaction conditions with short reaction times (15 min) and purification of the produced N-formamides is not needed.

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Synthesis and biological properties of macrolactam analogs of the natural product macrolide (−)-A26771B

Promising synthetic derivatives of macrolactone natural product (-)-A26771B have been designed and synthesized both from semisynthesis and total synthesis. Further optimization led to the first synthesis of macrolactam analogs of (-)-A26771B with improved antibacterial activity and metabolic stability.

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WO 2011058193: [1,5]-diazocin derivatives

Contribution from EDELRIS: The present invention relates to compounds having a [1,5]-diazocin, in particular a 4-oxo-[1,5]-diazocin, type of structure, to compositions and/or medicaments comprising at least one compound of this type, and their use as a constituent in a medicament, in particular for the treatment of diabetes, more particularly of non-insulin dependent diabetes mellitus (type II diabetes), insulin dependent diabetes mellitus (type I diabetes), and/or of hypertension, pre-diabetes, metabolic syndrome and obesity.

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Natural products and combinatorial chemistry: back to the future

The introduction of high-throughput synthesis and combinatorial chemistry has precipitated a global decline in the screening of natural products by the pharmaceutical industry. Some companies terminated their natural products program, despite the unproven success of the new technologies. This was a premature decision, as natural products have a long history of providing important medicinal agents. Furthermore, they occupy a complementary region of chemical space compared with the typical synthetic compound library. For these reasons, the interest in natural products has been rekindled. Various approaches have evolved that combine the power of natural products and organic chemistry, ranging from the combinatorial total synthesis of analogues to the exploration of natural product scaffolds and the design of completely unnatural molecules that resemble natural products in their molecular characteristics.

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