Servier Research Institute of Medicinal Chemistry

Budapest, Hungary

Servier Research Institute of Medicinal Chemistry

Budapest, Hungary
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PubMed | Monash University, Walter and Eliza Hall Institute of Medical Research, Vernalis, Servier Research Institute of Medicinal Chemistry and 2 more.
Type: Journal Article | Journal: Nature | Year: 2016

Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.

Sinai A.,Institute for Research In Catalysis | Vangel D.,Institute for Research In Catalysis | Gati T.,Servier Research Institute of Medicinal Chemistry | Bombicz P.,Hungarian Academy of Sciences | Novak Z.,Institute for Research In Catalysis
Organic Letters | Year: 2015

A copper-catalyzed carboarylation-ring-closure strategy was used for the modular synthesis of oxazolines via the reaction of 1-aryl- and 1-alkylpropargylamides and diaryliodonium salts. The novel approach enables the efficient, modular synthesis of oxazoline derivatives bearing fully substituted exo double bonds. © 2015 American Chemical Society.

Faigl F.,Budapest University of Technology and Economics | Faigl F.,Hungarian Academy of Sciences | Erdelyi Z.,Budapest University of Technology and Economics | Deak S.,Budapest University of Technology and Economics | And 2 more authors.
Tetrahedron Letters | Year: 2014

A highly efficient pyrrolidine-derived atropisomeric amino alcohol, (Sa)-1-[2-diphenylhydroxymethyl-6-(trifluoromethyl)phenyl]-2-(1-pyrrolido)methyl-1H-pyrrole, has been synthesized as a chiral ligand for the enantioselective addition of diethylzinc to some prochiral aldehydes to afford (S)-alcohols. The conversion rates were close to quantitative with good to excellent enantiomeric excesses (up to 95% ee). © 2014 Elsevier Ltd. All rights reserved.

Sinai A.,Institute for Research In Catalysis | Meszaros A.,Institute for Research In Catalysis | Gati T.,Servier Research Institute of Medicinal Chemistry | Kudar V.,Hungarian Academy of Sciences | And 2 more authors.
Organic Letters | Year: 2013

A new copper-catalyzed oxidative ring closure of ethynyl anilides with diaryliodonium salts was developed for the highly modular construction of benzoxazines bearing a fully substituted exo double bond. The oxidative transformation includes an unusual 6-exo-dig cyclization step with the formation of C-O and C-C bonds. © 2013 American Chemical Society.

Faigl F.,Budapest University of Technology and Economics | Faigl F.,Hungarian Academy of Sciences | Deak Sz.,Budapest University of Technology and Economics | Erdelyi Zs.,Budapest University of Technology and Economics | And 4 more authors.
Chirality | Year: 2015

Efficient synthesis of several new atropisomeric amino alcohols having 1-phenyl-1H-pyrrole skeleton are reported. Steric arrangements of the products were confirmed by a single-crystal X-ray measurement. The consequences of the size of the N-substituents on enantioinduction were examined by employing the enantioselective catalytic addition of diethylzinc to a series of substituted benzaldehydes (yields 91-97%, up to 85% enantiomeric excess). The special effect of the ortho methoxy group of the substrate on the enantioinduction is also interpreted. © 2014 Wiley Periodicals, Inc.

Lorincz K.,Eötvös Loránd University | Kotschy A.,Servier Research Institute of Medicinal Chemistry | Tammiku-Taul J.,University of Tartu | Sikk L.,University of Tartu | Burk P.,University of Tartu
Journal of Organic Chemistry | Year: 2010

Figure presented. The possible reaction pathways between methyllithium and disubstituted 1,2,4,5-tetrazines (bearing methyl, methylthio, phenyl, and 3,5-dimethylpyrazolyl groups) were investigated by means of the density functional theory B3LYP/6-31G* method. Solvation was modeled using the supermolecule approach, adding one tetrahydrofuran molecule to the complexes. Comparison of the calculated energies and structures for the alternate azaphilic and nucleophilic addition pathways showed that the azaphilic addition is kinetically favored over nucleophilic addition, while thermodynamically the nucleophilic addition is usually preferred. The coordination of the tetrazine molecule with methyllithium was found to play a crucial role in the process. These findings provide the first rationale for the experimentally observed unique reactivity of tetrazines toward polar organometallic reagents, suggesting the presence of a kinetically controlled process. © 2010 American Chemical Society.

PubMed | University of Bordeaux Segalen, Sevier Research Institute of Medicinal Chemistry, University of the Sciences in Philadelphia and Servier Research Institute of Medicinal Chemistry
Type: | Journal: Chemistry (Weinheim an der Bergstrasse, Germany) | Year: 2016

Metadynamics simulations were used to describe the conformational energy landscapes of several helically folded aromatic quinolinecarboxamide oligomers bearing a single chiral group at either the C- or N-terminus. The calculations allowed prediction of whether a helix handedness bias occurs under the influence of the chiral group and gave insight into the interactions - sterics, electrostatics, hydrogen bonds - responsible for a particular helix sense preference. In the case of camphanyl-based and morpholine-based chiral groups, experimental data confirming the validity of the calculations had already been available. New chiral groups with a proline residue were also investigated and predicted to induce handedness. This prediction was verified experimentally through the synthesis of proline-containing monomers, their incorporation into an oligoamide sequence via solid phase synthesis, and the investigation of handedness induction by NMR and circular dichroism (CD).

Gonda Z.,Eötvös Loránd University | Kovacs S.,Eötvös Loránd University | Weber C.,Servier Research Institute of Medicinal Chemistry | Gati T.,Servier Research Institute of Medicinal Chemistry | And 3 more authors.
Organic Letters | Year: 2014

Efficient copper-catalyzed trifluoromethylation of aromatic iodides was achieved with TMSCF3 in the presence of trimethylborate. The Lewis acid was used to anchor the in situ generated trifluoromethyl anion and suppress its rapid decomposition. Broad applicability of the new trifluoromethylating reaction was demonstrated in the functionalization of different aromatic and heteroaromatic iodides. © 2014 American Chemical Society.

Godsil B.P.,French Institute of Health and Medical Research | Godsil B.P.,University of Paris Pantheon Sorbonne | Kiss J.P.,Servier Research Institute of Medicinal Chemistry | Spedding M.,Les Laboratoires Servier | And 2 more authors.
European Neuropsychopharmacology | Year: 2013

While the hippocampal formation and the prefrontal cortex each have a well-established role in cognitive and mnemonic processes, the extent and manner in which these structures interact to achieve these functions has not been fully delineated. Recent research in rodents compellingly supports the idea that the projection of neurons extending from the CA1 region of the hippocampus and from the subiculum to the prefrontal cortex, referred to here as the H-PFC pathway, is critically involved in aspects of cognition related to executive function and to emotional regulation. Concurrently, it is becoming evident that persons suffering from schizophrenia, depression, and post-traumatic stress disorder display structural anomalies and aberrant functional coupling within the hippocampal-prefrontal circuit. Considering that these disorders involve varying degrees of cognitive impairment and emotional dysregulation, dysfunction in the H-PFC pathway might therefore be the common element of their pathophysiology. This overlap might also be intertwined with the pathway's evident susceptibility to stress and with its relationship to the amygdala. In consequence, the H-PFC pathway is a potentially crucial element of the pathophysiology of several psychiatric diseases, and it offers a specific target for therapeutic intervention, which is consistent with the recent emphasis on reframing psychiatric diseases in terms of brain circuits. © 2012 Elsevier B.V. and ECNP.

PubMed | Institute Of Recherches Servier and Servier Research Institute of Medicinal Chemistry
Type: Journal Article | Journal: Journal of medicinal chemistry | Year: 2016

7-Azaindole has been identified as a novel bidentate anchor point for allosteric glucokinase activators. A systematic investigation around three principal parts of the new small molecule glucokinase activators led to a robust SAR in agreement with structural data that also helped to assess the conformational flexibility of the allosteric activation site. The increase in glucose uptake resulting from glucokinase activation in hepatocytes in vitro translated into the efficient lowering of glucose levels in vivo with the best compounds.

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