A5045688828- Mast cells and histamine
- Receptor Mechanisms and Signaling
- Carbohydrate Chemistry and Synthesis
- Chemical Synthesis and Analysis
- Lysosomal Storage Disorders Research
- Computational Drug Discovery Methods
- Cellular transport and secretion
- Synthetic Organic Chemistry Methods
- Alzheimer's disease research and treatments
- Circadian rhythm and melatonin
- Crystallization and Solubility Studies
- Nuclear Receptors and Signaling
- Treatment of Major Depression
- Cholinesterase and Neurodegenerative Diseases
- Click Chemistry and Applications
- Protein Kinase Regulation and GTPase Signaling
- Fungal Biology and Applications
- Microbial Natural Products and Biosynthesis
- Enzyme Structure and Function
- Atrial Fibrillation Management and Outcomes
- Marine Sponges and Natural Products
- Hemophilia Treatment and Research
- Plant-Microbe Interactions and Immunity
- Cancer, Hypoxia, and Metabolism
- Machine Learning in Materials Science
Roche (Switzerland)
2007-2025
Mettler-Toledo (China)
2009
Abstract Background Amyloid-β peptide (Aβ) species of 42 or 43 amino acids in length (Aβ42/43) trigger Alzheimer´s disease (AD) and are produced abnormal amounts by mutants the γ-secretase subunit presenilin-1 (PS1), which represent primary cause familial AD (FAD). Lowering these peptides modulators (GSMs) is increasingly considered a safe strategy to treat since compounds do not affect overall cleavage substrates. GSMs were shown modulate only wild-type (WT) but also FAD mutants, expanding...
Abstract Erythromycin, avermectin and rapamycin are clinically useful polyketide natural products produced on modular synthase multienzymes by an assembly-line process in which each module of enzymes turn specifies attachment a particular chemical unit. Although encoding genes have been successfully engineered to produce novel analogues, the can be relatively slow, inefficient, frequently low-yielding. We now describe method for rapidly recombining gene clusters replace, add or remove...
Abstract Abnormal generation of neurotoxic amyloid‐β peptide (Aβ) 42/43 species due to mutations in the catalytic presenilin 1 ( PS 1) subunit γ‐secretase is major cause familial Alzheimer's disease FAD ). Deeper mechanistic insight on Aβ43 still lacking, and it unclear whether modulators GSM s) can reduce levels this Aβ species. By comparing several types Aβ43‐generating mutants, we observe that very high are often produced when function severely impaired. Altered interactions C99,...
Obesity is a major risk factor in the development of conditions such as hypertension, hyperglycemia, dyslipidemia, coronary artery disease, and cancer. Several pieces evidence across different species, including primates, underscore implication histamine 3 receptor (H3R) regulation food intake body weight potential therapeutic effect H3R inverse agonists. A pharmacophore model, based on public information validated by previous investigations, was used to design several scaffolds. Out these...
A fragment screening approach designed to target specifically the S-adenosyl-l-methionine pocket of catechol O-methyl transferase allowed identification structurally related fragments high ligand efficiency and with activity on described orthogonal assays. By use a reliable enzymatic assay together X-ray crystallography as guidance, series modifications revealed an SAR and, after several expansions, potent lead compounds could be obtained. For first time nonphenolic small low nanomolar...
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...
Starting from RO6800020 (1), our former γ-secretase modulator (GSM) lead compound, we utilized sequential structural replacements to improve the potency (IC50), pharmacokinetic properties including free fraction (fraction unbound (fu)) in plasma, and vivo efficacy. Importantly, used novel CF3-alkoxy groups as bioisosteric of a fluorinated phenyl ring such lipophilicity, solubility, metabolic stability, could be balanced, maintaining low Pgp efflux needed for CNS penetration. In addition, by...
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...
Obesity is a major risk factor for the development of conditions such as hypertension, hyperglycemia, dyslipidemia, coronary artery disease and cancer. Several pieces evidence, including data in primates, have demonstrated beneficial effects histamine-3 receptor (H3R) inverse agonists regulation food intake body weight. A pharmacophore model based on selected published H3R ligands validated by previous investigations, was used to identify 5-oxy-2-carboxamide-indole core novel series...