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Nov092017

New Caspase-1 inhibitor by scaffold hopping into bio-inspired 3D-fragment space

Virtual fragmentation of a library of 12,000 compounds inspired by natural products led to a dataset of 153,000 fragments that was used as a source to identify effective P2-P3 scaffold replacement solutions for peptidic Caspase-1 inhibitors. Our strategy led to the identification of an original 2-azabicyclo-octane scaffold (2-ABO) that was further elaborated into the potent Caspase-1 inhibitor CD10847 (IC50 = 17 nM). The crystal structure of Caspase-1 in complex with CD10847 was obtained, and its binding mode was shown to be similar to the one predicted by docking and in good agreement with other known inhibitors.

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Oct252017

Isoform-Selective ATAD2 Chemical Probe with Novel Chemical Structure and Unusual Mode of Action

ATAD2 (ANCCA) is an epigenetic regulator and transcriptional cofactor, whose overexpression has been linked to the progress of various cancer types. Here, we report a DNA-encoded library screen leading to the discovery of BAY-850, a potent and isoform selective inhibitor that specifically induces ATAD2 bromodomain dimerization and prevents interactions with acetylated histones in vitro, as well as with chromatin in cells. These features qualify BAY-850 as a chemical probe to explore ATAD2 biology.

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Oct052017

WO2017173049: Compounds for the inhibition of cyclophilins and uses thereof

Contribution from Edelris: the invention patented by Merck Serono relates to compounds, and pharmaceutically acceptable compositions thereof, useful as inhibitors of cyclophilins, and for the treatment of cyclophilin-related disorders.

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Oct052017

WO2017173048: Compounds for the inhibition of cyclophilins and uses thereof

Contribution from Edelris: the invention patented by Merck Serono relates to compounds, and pharmaceutically acceptable compositions thereof, useful as inhibitors of cyclophilins, and for the treatment of cyclophilin-related disorders.

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Jun082017

WO2017093272 : Furane derivatives as inhibitors of ATAD2

Contribution from Edelris: the invention patented by Bayer relates to furane derivatives as inhibitors of ATAD2 and processes for their preparation, their use for the treatment and/or prophylaxis of diseases, and their use for the preparation of pharmaceuticals for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of cancer.

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Dec192016

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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Nov292016

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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Jul082016

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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Nov242015

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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Nov232015

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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Nov232015

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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Jun032015

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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Jun022015

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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Jun012015

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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Mar092015

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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Feb232015

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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Feb112015

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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Jul282014

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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Jul152014

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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Mar012014

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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Sep282012

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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Feb012012

(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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Aug012011

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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Jun232011

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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May092011

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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May062004

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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