A5061526504- Protein Degradation and Inhibitors
- Asymmetric Synthesis and Catalysis
- Multiple Myeloma Research and Treatments
- Chemical synthesis and alkaloids
- Synthetic Organic Chemistry Methods
- Cancer Treatment and Pharmacology
- Computational Drug Discovery Methods
- Histone Deacetylase Inhibitors Research
- Machine Learning in Materials Science
- Tryptophan and brain disorders
- Chemical Synthesis and Analysis
- Catalytic Alkyne Reactions
- Bipolar Disorder and Treatment
- Stress Responses and Cortisol
- RNA Interference and Gene Delivery
- Quinazolinone synthesis and applications
- Acute Myeloid Leukemia Research
- Peptidase Inhibition and Analysis
- Metabolism, Diabetes, and Cancer
- X-ray Diffraction in Crystallography
- Alkaloids: synthesis and pharmacology
- Crystallization and Solubility Studies
- Crystallography and molecular interactions
- Cyclopropane Reaction Mechanisms
- Oxidative Organic Chemistry Reactions
Eurofins (France)
2024
Servier (France)
2013-2022
Institut des Hautes Études Scientifiques
2018-2022
GlaxoSmithKline (France)
2009-2017
Institut de Recherche de Chimie Paris
2016
Centre National de la Recherche Scientifique
2001-2016
Chimie ParisTech
2016
Université Paris Sciences et Lettres
2016
Molecular Discovery (United Kingdom)
2014
GlaxoSmithKline (United Kingdom)
2011-2014
Epigenetic mechanisms of gene regulation have a profound role in normal development and disease processes. An integral part this mechanism occurs through lysine acetylation histone tails which are recognized by bromodomains. While the biological structural characterization many bromodomain containing proteins has advanced considerably, therapeutic tractability protein family is only now becoming understood. This paper describes discovery molecular potent (nM) small molecule inhibitors that...
The bromo and extra C-terminal domain (BET) family of bromodomains are involved in binding epigenetic marks on histone proteins, more specifically acetylated lysine residues. This paper describes the discovery structure-activity relationships (SAR) potent benzodiazepine inhibitors that disrupt function BET (BRD2, BRD3, BRD4). work has yielded a potent, selective compound I-BET762 is now under evaluation phase I/II clinical trial for nuclear protein testis (NUT) midline carcinoma other cancers.
Through their function as epigenetic readers of the histone code, BET family bromodomain-containing proteins regulate expression multiple genes therapeutic relevance, including those involved in tumor cell growth and inflammation. bromodomain inhibitors have profound antiproliferative anti-inflammatory effects which translate into efficacy oncology inflammation models, first compounds now progressed clinical trials. The exciting biology BETs has led to great interest discovery novel...
Multi-parameter optimization (MPO) is a major challenge in new chemical entity (NCE) drug discovery. Recently, promising results were reported for deep learning generative models applied to de novo molecular design, but, our knowledge, until now no report was made of the value this technology addressing MPO an actual discovery project. In study, we demonstrate benefit applying AI real We evaluate potential ligand-based design using accelerate obtention lead compounds meeting 11 different...
Abstract Mycolactones are complex macrolides responsible for a severe necrotizing skin disease called Buruli ulcer. Deciphering their functional interactions is of fundamental importance the understanding, and ultimately, control this devastating mycobacterial infection. We report herein diverted total synthesis approach mycolactones analogues provide first insights into structure–activity relationship based on cytopathic assays L929 fibroblasts. The lowest concentration inducing effect was...
Soluble guanylate cyclase (sGC), the primary mediator of nitric oxide (NO) bioactivity, exists as reduced (NO-sensitive) and oxidized (NO-insensitive) forms. We tested hypothesis that cardiovascular protective effects NO-insensitive sGC activation would be potentiated under conditions oxidative stress compared to those NO-sensitive stimulation. The activator GSK2181236A [a low, non-depressor dose, a high dose which lowered mean arterial pressure (MAP) by 5-10 mmHg] equi-efficacious doses...
Abstract β‐Amino alcohols derived from natural amino acids have been used extensively as a powerful source of chirality. Transformation the hydroxy group these β‐amino into good leaving group, by using trifluoroacetic anhydride, led to rearranged in yields and with high enantiomeric excesses. This rearrangement has allowed transformation substituted prolinols 3‐hydroxypiperidines linear alcohols, issued acids, alcohols. Chirality, 2009. © 2009 Wiley‐Liss, Inc.
Bromodomains (BRDs) are small protein domains found in a variety of proteins that recognize and bind to acetylated histone tails. This binding affects chromatin structure facilitates the localisation transcriptional complexes specific genes, thereby regulating epigenetically controlled processes including gene transcription mRNA elongation. Inhibitors bromodomain extra-terminal (BET) BRD2-4 T, which prevent acetyl-modified tails, have shown therapeutic promise several diseases. We report...
Recently, we reported a novel role for KMO in the pathogenesis of acute pancreatitis (AP). A number inhibitors kynurenine 3-monooxygenase (KMO) have previously been described as potential treatments neurodegenerative conditions and particularly Huntington's disease. However, to date insufficient aqueous solubility relative their cellular potency be compatible with intravenous (iv) dosing route required AP. We identified optimized series high affinity favorable physicochemical properties. The...
Abstract The efficient gold‐catalyzed cyclization reactions of alkynyl silyl enol ethers were successfully applied to the preparation bicyclo[3.2.1]octanone derivatives. Accordingly, after optimization gold catalytic system, several bicyclic α,β‐unsaturated keto adducts synthesized in good excellent yields. process followed a major 5‐ exo via an anti addition ether π‐activated intermediate, which was demonstrated by deuterium incorporation experiment. A 6‐ endo observed for bearing...
A ring expansion and a radical dehalogenation have been used as the key steps in formal total synthesis of (−)-paroxetine. The substituted piperidine precursor (−)-paroxetine was generated by means stereoselective prolinol. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)
A ring expansion reaction applied to a substituted prolinol has been used in order obtain the piperidine core of (-)-velbanamine, an alkaloid extracted from Tabernaemontana eglandulosa.
AMP-activated protein kinase (AMPK) is an evolutionarily conserved fuel-sensing enzyme that activated in shortage of energy and suppressed its surfeit. AMPK activation stimulates fatty acid oxidation, enhances insulin sensitivity, alleviates hyperglycemia hyperlipidemia, inhibits proinflammatory changes. Thus, a well-received therapeutic target for type 2 diabetes other metabolic disorders. Here, we will report the discovery pyrrolopyridone derivatives as direct activators. We illustrate...
Multi-Parameter Optimization (MPO) is a major challenge in New Chemical Entity (NCE) drug discovery projects, and the inability to identify molecules meeting all criteria of lead optimization (LO) an important cause NCE project failure. Several ligand- structure-based de novo design methods have been published over past decades, some which proved useful multiobjective optimization. However, there still need for improvement better address chemical feasibility generated compounds as well...
Carnitine palmitoyl transferase 2 (CPT2) deficiency is one of the most common inherited fatty acid oxidation (FAO) defects and represents a prototypical mitochondrial metabolic myopathy. Recent studies have suggested pivotal role adenosine monophosphate-activated protein kinase (AMPK) in skeletal muscle plasticity homeostasis. Thus, we tested potential GSK773, novel direct AMPK activator, to improve or correct FAO capacities cells from patients harboring various mutations. We used controls'...
Hydrazinocyclohexadienes, easily prepared by an ene-reaction between commercially available azodicarboxylate reagents and cyclohexadiene, are interesting substrates for desymmetrization reactions. Under Sharpless asymmetric dihydroxylation conditions, they can lead efficiently to several chiral building blocks as well advanced precursors of biologically active compounds.
Multi-Parameter Optimization (MPO) is a major challenge in New Chemical Entity (NCE) drug discovery projects, and the inability to identify molecules meeting all criteria of lead optimization (LO) an important cause NCE project failure. Several ligand- structure-based de novo design methods have been published over past decades, some which proved useful multiobjective optimization. However, there still need for improvement better address chemical feasibility generated compounds as well...