A5023761649- Protein Degradation and Inhibitors
- Asymmetric Synthesis and Catalysis
- Osteoarthritis Treatment and Mechanisms
- Chemical Synthesis and Analysis
- Multiple Myeloma Research and Treatments
- Synthesis and Biological Evaluation
- Synthetic Organic Chemistry Methods
- Inflammatory mediators and NSAID effects
- Synthesis and bioactivity of alkaloids
- Chemical Reaction Mechanisms
- Protease and Inhibitor Mechanisms
- Cell Adhesion Molecules Research
- Receptor Mechanisms and Signaling
- Histone Deacetylase Inhibitors Research
- Chemical synthesis and alkaloids
- Ubiquitin and proteasome pathways
- Chronic Lymphocytic Leukemia Research
- Computational Drug Discovery Methods
- Crystallization and Solubility Studies
- Phosphodiesterase function and regulation
- Adenosine and Purinergic Signaling
- Coordination Chemistry and Organometallics
- Multicomponent Synthesis of Heterocycles
- Cystic Fibrosis Research Advances
- Cancer therapeutics and mechanisms
Galapagos (France)
2017-2024
GlaxoSmithKline (France)
2011-2014
Molecular Discovery (United Kingdom)
2014
GlaxoSmithKline (United Kingdom)
2014
University of Geneva
2000
Laboratoire de Chimie Organique
1991-1996
Sorbonne Université
1991-1996
Centre National de la Recherche Scientifique
1991-1994
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.
BET family proteins are epigenetic regulators known to control expression of genes involved in cell growth and oncogenesis. Selective inhibitors exhibit potent anti-proliferative activity a number hematologic cancer models, part through suppression the MYC oncogene downstream Myc-driven pathways. However, little is currently about solid tumor whether down-regulation contributes sensitivity. Here we provide evidence for inhibitor neuroblastoma, pediatric associated with high frequency MYCN...
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...
There are currently no approved disease-modifying osteoarthritis (OA) drugs (DMOADs). The aggrecanase ADAMTS-5 is key in the degradation of human aggrecan (AGC), a component cartilage. Therefore, promising target for identification DMOADs. We describe discovery GLPG1972/S201086, potent and selective inhibitor obtained by optimization hydantoin series following an HTS. Biochemical activity against rat was assessed via fluorescence-based assay. inhibitory confirmed with using AGC ELISA. most...
Medium chain fatty acids can activate the pro-inflammatory receptor GPR84 but so also molecules related to 3,3'-diindolylmethane. 3,3'-Diindolylmethane and decanoic acid acted as strong positive allosteric modulators of function each other analysis showed affinity 3,3'-diindolylmethane be at least 100 fold higher. Methyl decanoate was not an agonist GPR84. This implies a key role in binding for carboxylic acid. Via homology modelling we predicted confirmed integral arginine172, located 2nd...
GPR84 is a medium chain free fatty acid-binding G-protein-coupled receptor associated with inflammatory and fibrotic diseases. As the only reported antagonist of (PBI-4050) that displays relatively low potency selectivity, clear need exists for an improved modulator. Structural optimization hit 1, identified through high-throughput screening, led to identification potent selective inhibitor GLPG1205 (36). Compared initial hit, 36 showed in guanosine 5′-O-[γ-thio]triphosphate assay, exhibited...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTPreparation and Utilization of Chiral Dihydropyridines. Synthesis Indoloquinolizines BenzoquinolizinesPierre Mangeney, Romain Gosmini, Sabine Raussou, Monique Commercon, Alexandre AlexakisCite this: J. Org. Chem. 1994, 59, 7, 1877–1888Publication Date (Print):April 1, 1994Publication History Published online1 May 2002Published inissue 1 April 1994https://pubs.acs.org/doi/10.1021/jo00086a045https://doi.org/10.1021/jo00086a045research-articleACS...
Salt-inducible kinases (SIKs) SIK1, SIK2, and SIK3 are serine/threonine form a subfamily of the protein kinase AMP-activated (AMPK) family. Inhibition SIKs in stimulated innate immune cells mouse models has been associated with dual mechanism action consisting reduction pro-inflammatory cytokines an increase immunoregulatory cytokine production, suggesting therapeutic potential for inflammatory diseases. Following high-throughput screening campaign, subsequent hit to lead optimization...
Abstract
A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) is a key enzyme in degradation of cartilage osteoarthritis (OA). We report the pharmacological characterization GLPG1972/S201086, new, potent selective small-molecule ADAMTS5 inhibitor.
Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) protein. This epithelial anion channel regulates active transport of chloride and bicarbonate ions across membranes. Mutations result reduced surface expression CFTR channels with impaired functionality. Correctors are small molecules that support trafficking to increase its membrane expression. Such correctors can have different mechanisms action. Combinations may a further improved therapeutic...
Efficient routes to alpha-tert-butyl- and alpha-iso-propyl-ortho-hydroxybenzylamines 1a 1b are described. Highly enantioenriched were obtained by resolution of the methoxy derivatives 2 recrystallization salts formed with mandelic acid followed Lewis mediated demethylation. The chiral 1,3-amino alcohol has also been in an asymmetric synthesis key step a diastereoselective alkylation imine condensation o-anisaldehyde phenyl glycinol. absolute stereochemistry these 1,3-aminophenols was...
Organocopper reagents react with 1-acylpyridinium salts, bearing in the 3 position a chiral aminal [1-acyl-3-(trans-1,3-dimethyl-4, 5-diphenylimidazolidin-2-yl)pyridinium salts], to give after acidic hydrolysis 4-substituted 1-acyl-1, 4-dihydropyridine-3-carboxaldehydes high optical purity and good chemical yield.
<h3>Background</h3> Degradation of articular cartilage and alterations the underlying subchondral bone are hallmarks osteoarthritis (OA)<sup>1</sup>. A disintegrin metalloproteinase with thrombospondin motifs-5 (ADAMTS-5) is a key aggrecan-cleaving enzyme involved in this pathogenic process from earliest stages degradation<sup>2</sup> as such, an attractive drug target for development disease-modifying OA (DMOAD)<sup>3</sup>. <h3>Objectives</h3> In report we describe <i>in vitro</i> vivo</i>...
<h3>Background</h3> Aggrecan cleavage is an early process in cartilage degradation observed OA. As a result, aggrecanase inhibition attractive therapeutic strategy for the treatment of OA.<sup>1 2</sup> A disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5) playing key role catabolic events leading to OA.<sup>3</sup> We previously described pharmacological characterisation GLPG1972, potent, selective orally bioavailable ADAMTS-5 inhibitor showing anti-catabolic activity...