A5042034877- Hippo pathway signaling and YAP/TAZ
- Immune Response and Inflammation
- Mast cells and histamine
- NF-κB Signaling Pathways
- Receptor Mechanisms and Signaling
- Polyamine Metabolism and Applications
- Phenothiazines and Benzothiazines Synthesis and Activities
- Cancer-related gene regulation
- Chemical Synthesis and Analysis
- Mass Spectrometry Techniques and Applications
- Cancer therapeutics and mechanisms
- interferon and immune responses
- Adenosine and Purinergic Signaling
- Cytokine Signaling Pathways and Interactions
- Ubiquitin and proteasome pathways
- Diabetes Treatment and Management
- Antimicrobial Peptides and Activities
- Neuropeptides and Animal Physiology
- Protein Degradation and Inhibitors
- Phosphodiesterase function and regulation
- Genomics, phytochemicals, and oxidative stress
- Analytical Chemistry and Chromatography
- Metabolomics and Mass Spectrometry Studies
- Asthma and respiratory diseases
- Nitric Oxide and Endothelin Effects
Quantitative BioSciences
2020-2024
Merck & Co., Inc., Rahway, NJ, USA (United States)
2010-2022
Protein arginine methyltransferase 5 (PRMT5) belongs to a family of enzymes that regulate the posttranslational modification histones and other proteins via methylation arginine. Methylation is linked an increase in transcription regulates manifold functions such as signal transduction transcriptional regulation. PRMT5 has been shown be upregulated tumor environment several cancer types, inhibition activity was identified potential way reduce growth. Previously, four different modes were...
IRAK4 is a critical upstream kinase in the IL-1R/TLR signaling pathway. Inhibition of hypothesized to be beneficial treatment autoimmune related disorders. A screening campaign identified pyrazole class inhibitors that were determined by X-ray crystallography exhibit an unusual binding mode. SAR efforts focused on identification potent and selective inhibitor with good aqueous solubility rodent pharmacokinetics. Pyrazole C-3 piperidines well tolerated, N-sulfonyl analogues generally having...
Abstract Many tumor types harbor alterations in the Hippo pathway, including mesothelioma, where a high percentage of cases are considered YAP1/TEAD dependent. Identification autopalmitoylation sites hydrophobic palmitate pocket TEADs, which may be necessary for YAP1 protein interactions, has enabled modern drug discovery platforms to generate compounds that allosterically inhibit complex formation and transcriptional activity. We report characterization novel inhibitor MRK-A from an aryl...
We report the identification and synthesis of a series aminopyrimidin-4-one IRAK4 inhibitors. Through high throughput screening, an aminopyrimidine hit was identified modified via structure enabled design to generate new, potent, kinase selective pyrimidin-4-one chemotype. This chemotype is exemplified by compound 16, which has potent inhibition activity (IC50 = 27 nM) excellent selectivity (>100-fold against 99% 111 tested kinases), 31, displays 93 good rat bioavailability (F 42%).
A series of novel 2-piperidinopiperidine thiadiazoles were synthesized and evaluated as new leads histamine H3 receptor antagonists. The 4-(5-([1,4'-bipiperidin]-1'-yl)-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)morpholine (5u) displayed excellent potency ex vivo occupancy. Compound 5u was also in for antidiabetic efficacy STZ diet-induced obesity type 2 diabetic mice or 12 days. Non-fasting glucose levels significantly reduced compared with vehicle-treated mice. In addition, dose dependently...
Proxyfan is a histamine H3 receptor protean agonist that can produce spectrum of pharmacological effects including agonist, inverse and antagonist. We have discovered proxyfan (10 mg/kg orally) significantly improved glucose excursion after an ip tolerance test in either lean or high-fat/cholesterol diet-induced obese mice. It also reduced plasma levels comparable to metformin (300 nongenetic type 2 diabetes mouse model. The dose-dependent decrease correlated with inhibition ex vivo binding...
A novel series of spiroimidazolone-based antagonists the human glucagon receptor (hGCGR) has been developed. Our efforts have led to compound 1, N-((2H-tetrazol-5-yl)methyl)-4-((R)-1-((5r,8R)-8-(tert-butyl)-3-(3,5-dichlorophenyl)-2-oxo-1,4-diazaspiro[4.5]dec-3-en-1-yl)-4,4-dimethylpentyl)benzamide (SCH 900822), a potent hGCGR antagonist with exceptional selectivity over glucagon-like peptide-1 receptor. Oral administration 1 lowered 24 h nonfasting glucose levels in imprinting control region...
Background: Matrix-assisted laser desorption/ionization (MALDI)–tandem mass spectrometry (MS)/MS is a proven reliable tool for visualizing the spatial distribution of dosed drugs and their primary metabolites in animal tissue sections. Materials & methods: The rat brain sections coated with dihydroxybenzoic acid as matrix, were analyzed by MALDI–MS/MS imaging experiments. potential astemizole homogenate selected experiments first identified high-performance liquid chromatography coupled to...
<p>Characterization of HGF impact on MRK-A activity.</p>
<p>In vivo pathway analysis after MRK-A treatment.</p>
<p>Supplementary/extended materials and methods</p>
<p>In vitro characterization of MRK-A.</p>
<div>Abstract<p>Many tumor types harbor alterations in the Hippo pathway, including mesothelioma, where a high percentage of cases are considered YAP1/TEAD dependent. Identification autopalmitoylation sites hydrophobic palmitate pocket TEADs, which may be necessary for YAP1 protein interactions, has enabled modern drug discovery platforms to generate compounds that allosterically inhibit complex formation and transcriptional activity. We report characterization novel inhibitor...