A5072499797- Cannabis and Cannabinoid Research
- Pancreatic function and diabetes
- Computational Drug Discovery Methods
- Pharmacological Receptor Mechanisms and Effects
- Carbohydrate Chemistry and Synthesis
- Retinal and Macular Surgery
- Cellular transport and secretion
- Alzheimer's disease research and treatments
- Lipid metabolism and biosynthesis
- Cerebrovascular and genetic disorders
- Lysosomal Storage Disorders Research
- Neuroscience and Neuropharmacology Research
- Chemistry and Chemical Engineering
- Protein Structure and Dynamics
- GABA and Rice Research
- Cell Image Analysis Techniques
- Cancer, Lipids, and Metabolism
- Cholesterol and Lipid Metabolism
- Click Chemistry and Applications
- bioluminescence and chemiluminescence research
- Drug Transport and Resistance Mechanisms
- Forensic Toxicology and Drug Analysis
- Metabolomics and Mass Spectrometry Studies
- Neuroscience of respiration and sleep
- Receptor Mechanisms and Signaling
Roche (Switzerland)
2014-2025
The rapid and economical synthesis of novel bioactive compounds remains a significant hurdle in drug discovery efforts. This study demonstrates an integrated medicinal chemistry workflow that effectively diversifies hit lead structures, enabling efficient acceleration the critical hit-to-lead optimization phase. Employing high-throughput experimentation (HTE), we generated comprehensive data set encompassing 13,490 Minisci-type C-H alkylation reactions. served as foundation for training deep...
The rapid and economical synthesis of novel bioactive compounds remains a significant hurdle in drug discovery efforts. This study demonstrates an integrated medicinal chemistry workflow that effectively diversifies hit lead structures, enabling efficient acceleration the critical hit-to-lead optimization phase. Employing high-throughput experimentation (HTE), we generated comprehensive data set encompassing 13,490 Minisci-type C-H alkylation reactions. served as foundation for training deep...
Abstract Monoacylglycerol lipase (MAGL) is a key enzyme for signal termination in the endocannabinoid system (ECS). MAGL inhibition results indirect activation of cannabinoid receptors, which offers unique advantages treatment of, e.g., multiple sclerosis, epilepsy, and other neurological disorders. Molecular imaging techniques are valuable tools to overcome current poor understanding MAGL's distribution role patho‐ physiological processes within ECS signaling. Herein, we report design,...
Abstract Monoacylglycerol lipase (MAGL) is a key enzyme for signal termination in the endocannabinoid system (ECS). MAGL inhibition results indirect activation of cannabinoid receptors, which offers unique advantages treatment of, e.g., multiple sclerosis, epilepsy, and other neurological disorders. Molecular imaging techniques are valuable tools to overcome current poor understanding MAGL's distribution role patho‐ physiological processes within ECS signaling. Herein, we report design,...
Monoacylglycerol lipase (MAGL) is the pivotal catabolic enzyme responsible for signal termination in endocannabinoid system. Inhibition of MAGL offers unique advantages over direct activation cannabinoid receptors treating cancer, metabolic disorders, and inflammatory diseases. Although specific fluorescent molecular imaging probes are commonly used real-time analysis localization distribution drug targets cells, they almost invariably composed a linker connecting pharmacophore with large...
Sterile alpha and TIR Motif Containing 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD+) hydrolase that plays central role in programmed axonal degeneration. Axonal degeneration has been linked to neurodegenerative neurological disorders such as multiple sclerosis, amyotrophic lateral Parkinson's disease, peripheral neuropathies. Therefore, developing potent selective SARM1 inhibitors could be an effective strategy treat these disorders. We present herein the structure-guided discovery...
SARM1 has emerged as a promising therapeutic target in neurology due to its central role axonal degeneration and amenability different modes of small molecule inhibition. One chemical approach modulate involves orthosteric inhibition via SARM1-mediated base-exchange reaction between nicotinamide adenine dinucleotide (NAD), the substrate SARM1, generate active inhibitor. Here, we report that subinhibitory concentrations inhibitors (BEIs) paradoxically increase activity worsen SARM1-induced...
Monoacylglycerol lipase (MAGL) is one of the key enzymes in endocannabinoid system. Inhibition MAGL has been proposed as an attractive approach for treatment various diseases. In this study, we designed and successfully synthesized two series piperazinyl pyrrolidin-2-one derivatives novel reversible inhibitors. (R)-[18F]13 was identified through preliminary evaluation carbon-11-labeled racemic structures [11C]11 [11C]16. dynamic positron-emission tomography (PET) scans, showed a...
The antioxidant xanthophylls lutein and zeaxanthin are absorbed from the diet in a process involving lipoprotein formation. Selective mechanisms exist for their intestinal uptake tissue-selective distribution, but these poorly understood. We investigated role of high-density (HDL), apolipoprotein (apo) A1 ATP-binding cassette transporter (ABC) human polarized cell culture hamster model. Animals received dietary either liver X receptor (LXR) agonist or statin, which up- down-regulate ABCA1...
Monoacylglycerol lipase (MAGL) is a key enzyme involved in the metabolism of endogenous signaling ligand 2-arachidonoylglycerol, neuroprotective endocannabinoid intimately linked to central nervous system (CNS) disorders associated with neuroinflammation. In quest for novel MAGL inhibitors, focused screening approach on Roche library subset provided reversible benzoxazinone hit exhibiting high efficiency. The subsequent design three-dimensional
Abstract The human protease family HtrA is responsible for preventing protein misfolding and mislocalization, a key player in several cellular processes. Among these, HtrA1 implicated cancers, cerebrovascular disease age-related macular degeneration. Currently, activation not fully characterized relevant drug-targeting this protease. Our work provides mechanistic step-by-step description of regulation. We report that the trimer regulated by an allosteric mechanism which monomers relay signal...
Abstract Genetic, preclinical and clinical data link Parkinson's disease Gaucher's provide a rational entry point to modification therapy via enhancement of β‐Glucocerebrosidase (GCase) activity. We discovered new class pyrrolo[2,3‐b]pyrazine activators effecting both Vmax Km. They bind human GCase increase substrate metabolism in the lysosome cellular assay. obtained first crystal structure for an activator identified novel non‐inhibitory binding mode at interface dimer, rationalizing...
Abstract Cell‐free enzymatic assays are highly useful tools in early compound profiling due to their robustness and scalability. However, inadequacy reflect the complexity of target engagement a cellular environment may lead significantly divergent pharmacology that is eventually observed cells. The discrepancy emerges from properties like permeability unspecific protein binding largely mislead selection undergo further chemical optimization. We report development new intracellular NanoBRET...
The human genome encodes 518 protein kinases that are pivotal for drug discovery in various therapeutic areas such as cancer and autoimmune disorders. majority of kinase inhibitors target the conserved ATP-binding pocket, making it difficult to develop selective inhibitors. To characterize prioritize kinase-inhibiting candidates, efficient methods desired determine engagement across cellular kinome. In this study, we present CellEKT (Cellular Endogenous Kinase Targeting), an optimized robust...
Abstract Purpose The monoacylglycerol lipase (MAGL) plays a pivotal role in modulating the endocannabinoid system and is considered an attractive therapeutic target for diseases both central nervous periphery. current study aimed to develop evaluate suitable carbon-11 labeled tracer imaging MAGL preclinical studies. Methods ( R )-YH168 was synthesized via multi-step pathway its half-maximal inhibitory concentration IC 50 ) values were measured using enzymatic assay. Radiosynthesis of )-[ 11...
This study aimed to evaluate (<i>R</i>)-[<sup>18</sup>F]YH134 as a novel PET tracer for imaging monoacylglycerol lipase (MAGL). Considering the ubiquitous expression of MAGL throughout whole body, impact various inhibitors on brain uptake and its application in brain–periphery crosstalk were explored. <b>Methods:</b> knockout wild-type mice used in vitro autoradiography experiments. To explore peripheral occupancy uptake, kinetics with an arterial input function studied male Wistar rats...
Abstract Genetic, preclinical and clinical data link Parkinson's disease Gaucher's provide a rational entry point to modification therapy via enhancement of β‐Glucocerebrosidase (GCase) activity. We discovered new class pyrrolo[2,3‐b]pyrazine activators effecting both Vmax Km. They bind human GCase increase substrate metabolism in the lysosome cellular assay. obtained first crystal structure for an activator identified novel non‐inhibitory binding mode at interface dimer, rationalizing...
ABSTRACT The human protease family HtrA is responsible for preventing protein misfolding and mislocalization, a key player in several cellular processes. Among these, HtrA1 implicated cancers, cerebrovascular disease age-related macular degeneration. activation, although very relevant drug-targeting this protease, remains poorly characterized. Our work provides mechanistic step-by-step description of activation regulation. We report that the trimer regulated by an allosteric mechanism which...