A5052731255- HIV/AIDS drug development and treatment
- HIV Research and Treatment
- Hormonal Regulation and Hypertension
- Click Chemistry and Applications
- HIV-related health complications and treatments
- Pharmacological Effects of Natural Compounds
- Chemical Synthesis and Analysis
- Pneumocystis jirovecii pneumonia detection and treatment
- Gastrointestinal Tumor Research and Treatment
- Coenzyme Q10 studies and effects
- Pharmacogenetics and Drug Metabolism
- Aldose Reductase and Taurine
- Crystallization and Solubility Studies
- Photochemistry and Electron Transfer Studies
- X-ray Diffraction in Crystallography
- Synthesis and Biological Activity
- Eicosanoids and Hypertension Pharmacology
- Biochemical and Molecular Research
- Neurofibromatosis and Schwannoma Cases
- Computational Drug Discovery Methods
- Enzyme Structure and Function
- Radical Photochemical Reactions
- Organoboron and organosilicon chemistry
- Sarcoma Diagnosis and Treatment
- T-cell and Retrovirus Studies
Merck (Germany)
2020-2025
Boehringer Ingelheim (Germany)
2016
Philipps University of Marburg
1994-2015
Imperial College London
2010-2011
Kiel University
2003-2008
The University of Queensland
2008
University of Colorado Health
2004
University Hospital Schleswig-Holstein
2003
University of Lübeck
2003
University of Mississippi
2002
Accurate ranking of compounds with regards to their binding affinity a protein using computational methods is great interest pharmaceutical research. Physics-based free energy calculations are regarded as the most rigorous way estimate affinity. In recent years, many retrospective studies carried out both in academia and industry have demonstrated its potential. Here, we present results large-scale prospective application FEP+ method active drug discovery projects an setting at Merck KGaA,...
Cyclin-dependent protein kinases (CDKs) are central to the appropriate regulation of cell proliferation, apoptosis, and gene expression. Abnormalities in CDK activity common features cancer, making family members attractive targets for development anticancer drugs. Here, we report identification a pyrazolo[1,5-a]pyrimidine derived compound, 4k (BS-194), as selective potent inhibitor, which inhibits CDK2, CDK1, CDK5, CDK7, CDK9 (IC50 = 3, 30, 250, 90 nmol/L, respectively). Cell-based studies...
Background —Although endotoxin (lipopolysaccharides, LPS) is recognized as a mediator of septic cardiodepression, its cardiac effects are still not fully elucidated. Methods and Results —Perfusion isolated rat hearts with LPS for 180 minutes resulted in decline left ventricular contractility after 90 minutes, whereas coronary perfusion pressure remained unaffected. This cardiodepression was paralleled by release tumor necrosis factor (TNF)-α into the perfusate preceded myocardial TNF-α mRNA...
4-Oxonon-2-enal (4ONE) was demonstrated to be a product of lipid peroxidation, and previous studies found that it highly reactive toward DNA protein. The present study sought determine whether carbonyl reductase (CR) catalyzes reduction 4ONE, representing potential pathway for metabolism the peroxidation product. Recombinant CR cloned from human liver cDNA library, expressed in Escherichia coli, purified by metal chelate chromatography. Both 4ONE its glutathione conjugate were substrates CR,...
Abstract Primary activating mutations in KIT (exons 9/11) are key driver alterations about 80% of gastrointestinal stromal tumors (GIST). Imatinib, a small molecule tyrosine kinase inhibitor, is used successfully as first-line therapy for unresectable metastatic or recurrent GIST patients, but secondary resistance the domains frequently occur. Currently approved later-line therapies target these incompletely with limited clinical benefit. M4205, kinome-selective was designed to address this...
Abstract
3,4-disubstituted pyrrolidines originally designed to inhibit the closely related HIV-1 protease were evaluated as privileged structures against HTLV-1 (HTLV-1 PR). The most potent inhibitor of this series exhibits two-digit nanomolar affinity and represents, best our knowledge, nonpeptidic PR described so far. X-ray two representatives bound determined, structural basis their is discussed.
Infections with the human immunodeficiency virus, which inevitably lead to development of AIDS, are still among most serious global health problems causing more than 2.5 million deaths per year. In pathophysiological processes this pandemic, HIV protease has proven be an invaluable drug target because its essential role in virus' replication process. By use pyrrolidine as core structure, symmetric 3,4-bis-N-alkylsulfonamides were designed and synthesized enantioselectively from...
Abstract HIV protease is a well‐established drug target in antiviral chemotherapy. Immense research efforts have been made to discover effective inhibitors, thus making the enzyme one of most studied and best characterized proteins. Although exhibits high flexibility, all approved drugs virtually same protein conformation. The development viral cross‐resistance demands generation inhibitors with novel scaffolds deviating modes binding. Herein we report design short, high‐yielding...
The treatment of gastrointestinal stromal tumors (GISTs) driven by activating mutations in the KIT gene is a prime example targeted therapy for cancer. approval tyrosine kinase inhibitor imatinib has significantly improved patient survival, but emerging resistance under and relapse observed. Several additional inhibitors have been approved; still, there high unmet need with selectivity broad coverage all clinically relevant mutants. An imidazopyridine hit featuring excellent was identified...
Chiral 3,4-difunctionalized pyrrolidines, which can be derived from L-(+)- and D-(-)-tartaric acids, are useful versatile building blocks in total synthesis, catalyst preparation as well supramolecular medicinal chemistry. The of these azacycles, possible transformations their application described herein. Keywords: Tartaric Acids, C2-Symmetric Pyrrolidines, Chiral, Total Synthesis, Catalyst Design, Medicinal Chemistry
Plasmepsins II (EC number: 3.4.23.39) and IV 3.4.23.B14) are aspartic proteases present in the food vacuole of malaria parasite Plasmodium falciparum involved host hemoglobin degradation. A series pyrrolidine derivatives, originally synthesized as HIV-1 protease inhibitors, were tested for activity against plasmepsin (Plm). Inhibitors nanomolar range discovered Plm isoforms. Detailed studies carried out to identify putative binding modes that help explain underlying structure-activity...
The highly conserved catalytic sites in protein kinases make it difficult to identify ATP competitive inhibitors with kinome-wide selectivity. Serendipitously, during a dedicated fragment campaign for the focal adhesion kinase (FAK), scaffold that had lost its initial FAK affinity showed remarkable potency and selectivity serine-arginine-protein 1-3 (SRPK1-3). Non-conserved interactions uniquely structured hinge region of SRPK family were key drivers exclusive discovered hit....
Abstract This paper describes an approach towards the total synthesis of lactonamycin with elaboration a key pentacyclic unit. Key steps include benzyl bromide 8 in eight and 23 % overall yield starting from 4‐methoxyphenol; high‐yielding Suzuki coupling between boronic ester 9 ; Lewis acid mediated, intramolecular Friedel–Crafts acylation to obtain fused BCDEF ring core.
Abstract Syntheses (Schemes 1–3), negative solvatochromism (Table 1), cation‐induced halochromism 2), and chiro‐solvatochromism (Tables 3 4) of the new crown ether‐substituted chiral pyridinium N ‐phenolate betaine dyes 18a, b 28a, , each posessing four stereogenic centers, are described. The absolute configuration at centers has been confirmed by X‐ray crystal structure analysis intermediate phenol 14a (Figure 1). Solutions prepared addition monochiral amines amino alcohols to solutions...