Bénédicte Lallemand

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

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).

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

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.

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

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.

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

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.

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

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.

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

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.

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

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)

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

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.

5‐HT7 Receptor Antagonists with an Unprecedented Selectivity Profile

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.