A5007941572- Tryptophan and brain disorders
- Chemical Synthesis and Analysis
- Pharmacological Receptor Mechanisms and Effects
- Innovative Microfluidic and Catalytic Techniques Innovation
- Radical Photochemical Reactions
- Bipolar Disorder and Treatment
- Synthesis and Catalytic Reactions
- Computational Drug Discovery Methods
- Receptor Mechanisms and Signaling
- Asymmetric Hydrogenation and Catalysis
- Air Traffic Management and Optimization
- UAV Applications and Optimization
- Click Chemistry and Applications
- Organophosphorus compounds synthesis
- Neuroendocrine regulation and behavior
- Synthetic Organic Chemistry Methods
- Catalytic C–H Functionalization Methods
- Satellite Communication Systems
- Multiple Myeloma Research and Treatments
- Neuroscience of respiration and sleep
- Immune cells in cancer
- Catalytic Cross-Coupling Reactions
- Analytical Chemistry and Chromatography
- Machine Learning in Materials Science
- Organic and Inorganic Chemical Reactions
Merck & Co., Inc., Rahway, NJ, USA (United States)
2016-2024
Airbus (Germany)
2022
Pfizer (United Kingdom)
2009-2012
University of Kaiserslautern
2011
Pfizer (United States)
2010
University of Manchester
2000-2001
University of Milan
1998
The posttranslational modification of chromatin through acetylation at selected histone lysine residues is governed by acetyltransferases (HATs) and deacetylases (HDACs). significance this subset the epigenetic code interrogated interpreted an acetyllysine-specific protein-protein interaction with bromodomain reader modules. Selective inhibition bromo extra C-terminal domain (BET) family bromodomains a small molecule feasible, may represent opportunity for disease intervention recently...
Indoleamine-2,3-dioxygenase 1 (IDO1) inhibition and its combination with immune checkpoint inhibitors like pembrolizumab have drawn considerable attention from both academia the pharmaceutical industry. Here, we describe discovery of a novel class highly potent IDO1 heme-displacing featuring unique bicyclo[1.1.1]pentane motif. Compound 1, evolving an ALIS (automated ligand identification system) hit, exhibited excellent potency but lacked desired pharmacokinetic profile due to extensive...
Ni/photoredox (4DPAIPN) dual catalysis enabled challenging peptide C(sp2)-O coupling reactions. Successful cross-coupling reactions were demonstrated with highly functionalized alcohols including side chains of amino acids (i.e., serine, threonine, tyrosine), trans-4-hydroxy-l-proline, alkyl alcohols, alkynylated and carbohydrates. Coupling between bromobenzoyl-capped peptides containing various either a protected serine building block or serine-containing dipeptide also proceeded...
Checkpoint inhibitors have demonstrated unprecedented efficacy and are evolving to become standard of care for certain types cancers. However, low overall response rates often hamper the broad utility potential these breakthrough therapies. Combination therapy strategies currently under intensive investigation in clinic, including combination PD-1/PD-L1 agents with IDO1 inhibitors. Here, we report discovery a class heme-binding featuring unique amino-cyclobutarene motif, which was discovered...
Continuous flow has been used widely in process chemistry and academic settings for various applications. However, initial reaction discovery generally remained "batch-exclusive" despite the existence of efficient, reproducible systems. We hereby disclose a workflow to bridge gap between early medicinal efforts process-scale development, showcased by optimization metallaphotoredox-catalyzed cross-coupling benzylic chlorides aryl bromides, followed two library syntheses complex drug-like compounds.
A practical protocol was developed that allows performing decarboxylative cross-coupling reactions in continuous flow reactors. Various biaryls were thus synthesized from aromatic carboxylic acids and aryl triflates using a Cu/Pd-catalyst system.
Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as a target of significant interest to the field cancer immunotherapy, upregulation IDO1 in certain cancers been linked host immune evasion and poor prognosis for patients. In particular, inhibition is combination therapy with checkpoint inhibition. Through an Automated Ligand Identification System (ALIS) screen, diamide class compounds was identified promising lead IDO1. While hit 1 possessed attractive cell-based potency, it suffered from...
Crohn's disease (CD) is a chronic disorder of the gastrointestinal tract characterized by inflammation and intestinal epithelial injury. Loss function mutations in intracellular bacterial sensor NOD2 are major risk factors for development CD. In absence robust recognition an inflammatory cascade initiated through alternative PRRs leading to present study, MCC950, specific small molecule inhibitor NLR pyrin domain-containing protein 3 (NLRP3), abrogated dextran sodium sulfate (DSS)-induced...
Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as an attractive target for cancer immunotherapy. An automated ligand identification system screen afforded the tetrahydroquinoline class of novel IDO1 inhibitors. Potency and pharmacokinetic (PK) were key issues with this compounds. Structure-based drug design strategic incorporation polarity enabled rapid improvement on potency, solubility, oxidative metabolic stability. Metabolite studies revealed that amide hydrolysis in D-pocket was...
The clinical success of anti-IL-17 monoclonal antibodies (i.e., Cosentyx and Taltz) has validated Th17 pathway modulation for the treatment autoimmune diseases. nuclear hormone receptor RORγt is a master regulator cells affects production host cytokines, including IL-17A, IL-17F, IL-22, IL-26, GM-CSF. Substantial interest been spurred across both academia industry to seek small molecules suitable inhibition. A variety inhibitors have reported in past few years, majority which are orthosteric...
3,3-Disubstituted oxetanes have been utilized as bioisosteres for gem-dimethyl and cyclobutane functionalities. We report the discovery of a novel class oxetane indole-amine 2,3-dioxygenase (IDO1) inhibitors suitable Q3W (once every 3 weeks) oral parenteral dosing. A diamide IDO was discovered through an automated ligand identification system (ALIS). Installation fluorophenyl dramatically improved potency. Identification biaryl moiety unconventional amide isostere addressed metabolic...
The construction of complex aza-cycles is interest to drug discovery due the prevalence nitrogen-containing heterocycles in pharmaceutical agents. Herein we report an intramolecular C-H amination approach afford value-added and complexity-enriched bridged bicyclic amines. Guided by density functional theory nuclear magnetic resonance investigations, determined unique roles light heat activation bicyclization mechanism. We applied both a synergistic fashion, achieving gram-scale aza-cycle synthesis.
A new method to access cyclic peptidomimetics via a Pd-catalyzed macroamination reaction is presented. Natural amino acid amines are revealed as proficient coupling partners in these transformations. With commercially available CPhos G3 catalyst system and substrates bearing diverse aryl halide backbones, the unique head side-chain (or mimic) macrocycles afforded with ring sizes from 11 23 members yields up 84%.
As more macrocycle structures are utilized to drug intracellular targets, new platforms needed facilitate the discovery of cell permeable compounds in this unique chemical space. Herein, a method is disclosed that allows for efficient synthesis and permeability evaluation novel organo-peptide libraries. Thoughtful library design collection crude data using supercritical fluid chromatography mass spectrometry (SFC-MS) (EPSA) by mass-encoding stereochemistry, ring size, organic linker desired...
Mutant isocitrate dehydrogenase 1 (IDH1) has been identified as an attractive oncology target for which >70% of grade II and III gliomas ∼10% acute myeloid leukemia (AML) harbor somatic IDH1 mutations. These mutations confer a neomorphic gain function, leading to the production oncometabolite (R)-2-hydroxyglutarate (2-HG). We developed potent, selective, orally bioavailable brain-penetrant tricyclic diazepine scaffold that inhibits mutant IDH1. During course in vitro metabolism studies,...
Technological progress and economic interest are paving the way toward a more densified airspace. Seen as technical system composed of air vehicles, traffic control, service providers, airspace is expected to evolve significantly digitalized autonomous version its current self. In such future system, connectivity plays key role, needs be dependable secure. Regulation bodies have already defined set requirements, called required communication performance (RCP), against which links must...