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Featured researches published by Bénédicte Lallemand.


Bioorganic & Medicinal Chemistry Letters | 2002

First dual NK1 antagonists–serotonin reuptake inhibitors: synthesis and SAR of a new class of potential antidepressants

Thomas Ryckmans; Laurent Balancon; Olivier Berton; Christophe Genicot; Yves Lamberty; Bénédicte Lallemand; Patrick Pasau; Nathalie Pirlot; Luc Quere; Patrice Talaga

Compounds combining NK(1) antagonism and serotonin reuptake inhibition are described, and potentially represent a new generation of antidepressants. Compound 24 displays good affinities for both the NK(1) receptor and the serotonin reuptake site (32 and 25 nM, respectively).


Bioorganic & Medicinal Chemistry Letters | 2009

Discovery of 4-Azaindoles as Novel Inhibitors of C- met Kinase.

John B. Porter; Simon Lumb; Richard Jeremy Franklin; Jose M. Gascon-Simorte; Mark Daniel Calmiano; Kelly Le Riche; Bénédicte Lallemand; Jean Keyaerts; Helen Edwards; Alison Maloney; Jean Delgado; Lloyd M. King; Anne Marie Foley; Fabien Claude Lecomte; James Thomas Reuberson; Christoph Meier; Mark James Batchelor

A series of 4-azaindole inhibitors of c-Met kinase is described. The postulated binding mode was confirmed by an X-ray crystal structure and series optimisation was performed on the basis of this structure. Future directions for series development are discussed.


Journal of Medicinal Chemistry | 2008

4-Benzyl-1H-imidazoles with Oxazoline Termini as Histamine H3 Receptor Agonists

Maikel Wijtmans; Sylvain Celanire; Erwin Snip; Michel Gillard; Edith Gelens; Philippe Collart; Bastiaan J. Venhuis; Bernard Christophe; Saskia Hulscher; Henk van der Goot; Florence Lebon; Henk Timmerman; Remko A. Bakker; Bénédicte Lallemand; Rob Leurs; Patrice Talaga; Iwan J. P. de Esch

Research on the therapeutic applications of the histamine H3 receptor (H3R) has traditionally focused on antagonists/inverse agonists. In contrast, H3R agonists have received less attention despite their potential use in several disease areas. The lower availability of H3R agonists not only hampers their full therapeutic exploration, it also prevents an unequivocal understanding of the structural requirements for H3R activation. In the light of these important issues, we present our findings on 4-benzyl-1H-imidazole-based H3R agonists. Starting from two high throughput screen hits (10 and 11), the benzyl side chain was altered with lipophilic groups using combinatorial and classical chemical approaches (compounds 12-31). Alkyne- or oxazolino-substituents gave excellent affinities and agonist activities up to the single digit nM range. Our findings further substantiate the growing notion that basic ligand sidechains are not necessary for H 3R activation and reveal the oxazolino group as a hitherto unexplored functional group in H3R research.


ChemMedChem | 2014

Discovery of Heterocyclic Nonacetamide Synaptic Vesicle Protein 2A (SV2A) Ligands with Single-Digit Nanomolar Potency: Opening Avenues towards the First SV2A Positron Emission Tomography (PET) Ligands

Joël Mercier; Laurence Archen; Véronique Bollu; Stéphane Carré; Yves Evrard; Eric Jnoff; Benoit Kenda; Bénédicte Lallemand; Philippe Michel; Florian Montel; Florence Moureau; Nathalie Price; Yannick Quesnel; Xavier Sauvage; Anne Valade; Laurent Provins

The role of the synaptic vesicle protein 2A (SV2A) protein, target of the antiepileptic drug levetiracetam, is still mostly unknown. Considering its potential to provide in vivo functional insights into the role of SV2A in epileptic patients, the development of an SV2A positron emission tomography (PET) tracer has been undertaken. Using a 3D pharmacophore model based on close analogues of levetiracetam, we report the rationale design of three heterocyclic non‐acetamide lead compounds, UCB‐A, UCB‐H and UCB‐J, the first single‐digit nanomolar SV2A ligands with suitable properties for development as PET tracers.


ChemMedChem | 2010

Phenyl-oxazoles, a New Family of Inverse Agonists at the H3 Histamine Receptor

Frédéric Denonne; Franck Atienzar; Sylvain Celanire; Bernard Christophe; Frédérique Delannois; Christel Delaunoy; Marie-Laure Delporte; Véronique Durieu; Michel Gillard; Bénédicte Lallemand; Yves Lamberty; Geneviève Lorent; Alain Vanbellinghen; Nathalie Van houtvin; Valérie Verbois; Laurent Provins

Biogenic amines, such as histamine, are very important in human physiology. In particular, histamine is implicated in allergy (H1 receptor), [1] gastric secretion (H2R), [2] sleep/wake cycles or cognition (H3R) [3] and inflammatory/immunological processes (H4R). [4] The cloning and characterisation of H3R [5] have allowed many pharmaceutical companies to run highthroughput screening (HTS) campaigns and successfully come up with drug candidates. Pfizer, Sanofi-Aventis and Cephalon all currently have a compound in phase I clinical trials (PF3654746, SAR-110894, and CEP-26401 for Alzheimer’s disease). Moreover GlaxoSmithKline, Johnson & Johnson, Bioprojet, Transtech and Schering-Plough each have a compound in phase II (GSK-239512, BF2.649 and JNJ-31001074 as cognition enhancers, 9] SCH-497079 and HPP-404 against obesity, and BF2.649 for schizophrenia). A phase II study on another compound, GSK-189254, for the treatment of narcolepsy has recently been terminated. Several other candidates are in preclinical development or have reached some point in development for which results are expected in the near future.


ChemMedChem | 2009

Discovery of a new class of non-imidazole oxazoline-based histamine H(3) receptor (H(3)R) inverse agonists

Sylvain Celanire; Maikel Wijtmans; Bernard Christophe; Philippe Collart; Iwan de Esch; Donald Dassesse; Christel Delaunoy; Frédéric Denonne; Véronique Durieu; Edith Gelens; Michel Gillard; Bénédicte Lallemand; Yves Lamberty; Florence Lebon; Jean-Marie Nicolas; Luc Quere; Erwin Snip; Alain Vanbellinghen; Nathalie Van houtvin; Valérie Verbois; Henk Timmerman; Patrice Talaga; Rob Leurs; Laurent Provins

H3R inverse agonists based on an aminopropoxy‐phenyloxazoline framework constitute highly valuable druglike lead compounds that display efficacy in a mouse model of recognition memory.


ChemMedChem | 2010

Discovery of Indolone Acetamides as Novel SV2A Ligands with Improved Potency Toward Seizure Suppression

Anne Frycia; Jean-Philippe Starck; Sophie Jadot; Bénédicte Lallemand; Karine Leclercq; Patrick Lo Brutto; Alain Matagne; Valérie Verbois; Joël Mercier; Benoit Kenda

A major goal in epilepsy research is to develop new antiepileptic drugs (AEDs) that combine improved seizure control with enhanced tolerability while avoiding drug–drug interactions. Although the prognosis for seizure control is acceptable in up to 70 % of patients, approximately 30 % suffer from intractable pharmaco-resistant epilepsy. 3] Furthermore, the clinical use of most older AEDs is hampered by their limited tolerability; this most commonly consists of CNS-related adverse effects, idiosyncratic reactions such as skin rashes, and the potential for unfavorable drug–drug interactions. It was previously reported that the AED levetiracetam (2 ; Keppra ) has a unique brainspecific binding site. This site was recently identified as the synaptic vesicle protein 2A (SV2A). A strong correlation between the affinity of levetiracetam analogues for SV2A and their anti-seizure potency in the audiogenic mouse model of epilepsy has been reported. This suggests that levetiracetam’s interaction with SV2A has a major functional role in its anticonvulsant mechanism of action. SV2, a protein specific to synaptic vesicles, is a 12-transmembrane region glycoprotein present in all neural cells, and it is present in three isoforms: SV2A, SV2B, and SV2C. SV2A is the most widely distributed isoform and is ubiquitous in the CNS, but is also present in endocrine cells. Although the exact molecular role of SV2A is still unknown, it is believed to play a role in the exocytosis of neurotransmitters and to act as a modulator of vesicle fusion. Given the proven clinical efficacy of levetiracetam as an AED, its unique mechanism of action, and its excellent tolerability, we decided to initiate a drug discovery program focused on SV2A as a novel molecular target. The aim was to identify a new generation of SV2A ligands with an equal or better tolerability profile than 2 and an improved potency toward seizure suppression in animal models. At the outset of our work in the SV2A field, we systematically investigated the various positions of the pyrrolidone acetamide scaffold of 2. Among others, we discovered the importance of the carboxamide moiety on 2 and the preferred substitution position a to the carboxamide. This research lead to the identification of two compounds currently in clinical development: brivaracetam (3) and seletracetam (4), both of which are more potent than 2 in vitro toward SV2A and in vivo as anticonvulsant agents in audiogenic seizure-prone mice. (Figure 1)


Chemistry: A European Journal | 2017

C−H Cyanation of 6-Ring N-Containing Heteroaromatics

Bryony L. Elbert; Alistair J. M. Farley; Timothy W. Gorman; Tarn C. Johnson; Christophe Genicot; Bénédicte Lallemand; Patrick Pasau; Jakub Flasz; José L. Castro; Malcolm MacCoss; Robert S. Paton; Christopher J. Schofield; Martin D. Smith; Michael C. Willis; Darren J. Dixon

Abstract Heteroaromatic nitriles are important compounds in drug discovery, both for their prevalence in the clinic and due to the diverse range of transformations they can undergo. As such, efficient and reliable methods to access them have the potential for far‐reaching impact across synthetic chemistry and the biomedical sciences. Herein, we report an approach to heteroaromatic C−H cyanation through triflic anhydride activation, nucleophilic addition of cyanide, followed by elimination of trifluoromethanesulfinate to regenerate the cyanated heteroaromatic ring. This one‐pot protocol is simple to perform, is applicable to a broad range of decorated 6‐ring N‐containing heterocycles, and has been shown to be suitable for late‐stage functionalization of complex drug‐like architectures.


ChemMedChem | 2018

5‐HT7 Receptor Antagonists with an Unprecedented Selectivity Profile

Ali Ates; Pierre Burssens; Olivier Lorthioir; Patrick Lo Brutto; Gwenael Dehon; Jean Keyaerts; Francis Coloretti; Bénédicte Lallemand; Valérie Verbois; Michel Gillard; Céline Vermeiren

Selective leads: In this study, we generated a new series of serotonin 5-HT7 receptor antagonists. Their synthesis, structure-activity relationships, and selectivity profiles are reported. This series includes 5-HT7 antagonists with unprecedented high selectivity for the 5-HT7 receptor, setting the stage for lead optimization of drugs acting on a range of neurological targets.


Journal of Medicinal Chemistry | 2004

Discovery of 4-substituted pyrrolidone butanamides as new agents with significant antiepileptic activity.

Benoit Kenda; Alain Matagne; Patrice Talaga; Patrick Pasau; Edmond Differding; Bénédicte Lallemand; Anne Frycia; Florence Moureau; Henrik Klitgaard; Michel Gillard; Bruno Fuks; Philippe Michel

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