A5089924729- Receptor Mechanisms and Signaling
- Chemokine receptors and signaling
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Chemical synthesis and alkaloids
- Monoclonal and Polyclonal Antibodies Research
- Carbohydrate Chemistry and Synthesis
- Computational Drug Discovery Methods
- Pancreatic function and diabetes
- Lipoproteins and Cardiovascular Health
- RNA Interference and Gene Delivery
- RNA Research and Splicing
- Cancer Treatment and Pharmacology
- Biochemical Acid Research Studies
- Coordination Chemistry and Organometallics
- Phosphodiesterase function and regulation
- Eicosanoids and Hypertension Pharmacology
- Drug Transport and Resistance Mechanisms
- Heart Failure Treatment and Management
- Pluripotent Stem Cells Research
- Glycosylation and Glycoproteins Research
- Microbial Metabolic Engineering and Bioproduction
- Cytokine Signaling Pathways and Interactions
- Chemical Synthesis and Analysis
- Neuroscience and Neuropharmacology Research
Pfizer (United States)
2012-2023
Colorado State University
2013
AstraZeneca (United States)
2011
A compact and stable bicyclic bridged ketal was developed as a ligand for the asialoglycoprotein receptor (ASGPR). This compound showed excellent efficiency, molecular details of binding were revealed by first X-ray crystal structures ligand-bound ASGPR. analogue used to make potent di- trivalent binders Extensive characterization function these compounds rapid ASGPR-dependent cellular uptake in vitro high levels liver/plasma selectivity vivo. Assessment biodistribution rodents prototypical...
The asialoglycoprotein receptor (ASGPR) is a high-capacity galactose-binding expressed on hepatocytes that binds its native substrates with low affinity. More potent ligands are of interest for hepatic delivery therapeutic agents. We report several classes galactosyl analogues varied substitution at the anomeric, C2-, C5-, and C6-positions. Significant increases in binding affinity were noted trifluoromethylacetamide derivatives without covalent attachment to protein. A variety new obtained...
This manuscript describes an enantioselective synthesis of the naturally occurring alkaloid citrinadin B. The synthetic effort revealed anomaly in original structural assignment that has led to proposal a stereochemical revision. revision is consistent with structures previously reported for closely related family alkaloids, PF1270A-C. convergent and employs stereoselective intermolecular nitrone cyloaddition reaction as key step.
The chemokine receptor CXCR7 is an attractive target for a variety of diseases. While several small-molecule modulators have been reported, peptidic macrocycles may provide advantages in terms potency, selectivity, and reduced off-target activity. We produced series that incorporate N-linked peptoid functionality where the group enabled us to explore side-chain diversity well beyond natural amino acids. At same time, theoretical calculations experimental assays were used track reduce...
Acetyl-CoA carboxylase (ACC) catalyzes the rate-determining step in de novo lipogenesis and plays a crucial role regulation of fatty acid oxidation. Alterations lipid metabolism are believed to contribute insulin resistance; thus inhibition ACC offers promising option for intervention type 2 diabetes mellitus. Herein we disclose series inhibitors based on spirocyclic pyrazololactam core. The lactam has improved chemical metabolic stability relative our previously reported pyrazoloketone...
The synthesis of 4',6'-dihydrospiro[piperidine-4,5'-pyrazolo[3,4-c]pyridin]-7'(2'H)-one-based acetyl-CoA carboxylase inhibitors is reported. hitherto unknown N-2 tert-butyl pyrazolospirolactam core was synthesized from ethyl 3-amino-1H-pyrazole-4-carboxylate in a streamlined 10-step requiring only one chromatography procedure. described synthetic strategy provides pyrazolo-fused spirolactams halogenated benzylic arenes and cyclic carboxylates. Key steps include regioselective pyrazole...
C-X-C chemokine receptor type 7 (CXCR7) is involved in cardiac and immune pathophysiology. We report the discovery of a novel 1,4-diazepine CXCR7 modulator, demonstrating for first time role pharmacological intervention repair. Structure-activity-relationship (SAR) studies demonstrated that net reduction lipophilicity (log D) an incorporation saturated ring systems yielded compounds with good potencies improvements oxidative metabolic stability human-liver microsomes (HLM). Tethering...
The atypical chemokine receptor CXCR7 has been studied in various disease settings including immunological diseases and heart disease. Efforts to elucidate the role of have limited by lack suitable chemical tools with a range pharmacological profiles. A high-throughput screen was conducted discover novel matter potential modulate activity. This led identification series diphenylacetamides confirmed CXCL12 competition assay indicating binding. Further evaluation this revealed activity...
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