A5018547762- Synthetic Organic Chemistry Methods
- Asymmetric Synthesis and Catalysis
- Hepatitis C virus research
- Inflammasome and immune disorders
- HIV/AIDS drug development and treatment
- Gender, Security, and Conflict
- Gout, Hyperuricemia, Uric Acid
- Tryptophan and brain disorders
- Computational Drug Discovery Methods
- Hepatitis B Virus Studies
- Advanced Synthetic Organic Chemistry
- Monoclonal and Polyclonal Antibodies Research
- Pharmacogenetics and Drug Metabolism
- Biochemical and Molecular Research
- Amyotrophic Lateral Sclerosis Research
- Cancer therapeutics and mechanisms
- Traditional and Medicinal Uses of Annonaceae
- International Development and Aid
- RNA Research and Splicing
- Marine Sponges and Natural Products
- interferon and immune responses
- Ion Channels and Receptors
- Pharmacological Receptor Mechanisms and Effects
- Cancer, Stress, Anesthesia, and Immune Response
- Peacebuilding and International Security
Novartis (Switzerland)
2021-2025
Novartis Institutes for BioMedical Research
2025
Merck & Co., Inc., Rahway, NJ, USA (United States)
2008-2010
University of Cambridge
2001-2005
University of Edinburgh
1996-1999
NLRP3 is a molecular sensor recognizing wide range of danger signals. Its activation leads to the assembly an inflammasome that allows for caspase-1 and subsequent maturation IL-1β IL-18, as well cleavage Gasdermin-d pyroptotic cell death. The has been implicated in plethora diseases including gout, type 2 diabetes, atherosclerosis, Alzheimer's disease, cancer. In this publication, we describe discovery novel, tricyclic, NLRP3-binding scaffold by high-throughput screening. hit (1) could be...
The effects of mutation key active-site residues (Arg-47, Tyr-51, Phe-42 and Phe-87) in Bacillus megaterium flavocytochrome P450 BM3 were investigated. Kinetic studies on the oxidation laurate arachidonate showed that side chain Arg-47 contributes more significantly to stabilization fatty acid carboxylate than does Tyr-51 (kinetic parameters for laurate: R47A mutant, Km 859 µM, kcat 3960 min-1; Y51F 432 6140 wild-type, 288 5140 min-1). A slightly increased Y51F-catalysed is probably due...
Activation of the NLRP3 inflammasome in response to danger signals is a key innate immune mechanism and results production pro-inflammatory cytokines interleukin-1β (IL-1β) interleukin-18 (IL-18) as well pyroptotic cell death. Aberrant activation has been linked many acute chronic conditions ranging from atherosclerosis Alzheimer's disease cancer, based on clinical success IL-1-targeting therapies, emerged an attractive therapeutic target. Herein we describe our discovery, characterization,...
Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies in urgent demand. The polymerase of HCV is responsible the replication viral genome and has been prime target drug discovery efforts. Here, we report on further development tetracyclic indole inhibitors, binding to an allosteric site thumb domain. Structure−activity relationship (SAR) studies around indolo-benzoxazocine scaffold led identification compound 33 (MK-3281), inhibitor...
An expedient total synthesis of aurisides A and B (1), unusual cytotoxic macrolide glycosides isolated from the Japanese sea hare D. auricularia, takes advantage a highly convergent aldol-based route for stereocontrolled construction common core. This is followed by α-selective glycosylation to introduce sugar moieties. Aurisides (1) (2) are unique marine polyketides in 1996 Yamada co-workers Dolabella auricularia,1a an organism that has proved be rich source bioactive secondary...
The effects of mutation key active-site residues (Arg-47, Tyr-51, Phe-42 and Phe-87) in Bacillus megaterium flavocytochrome P450 BM3 were investigated. Kinetic studies on the oxidation laurate arachidonate showed that side chain Arg-47 contributes more significantly to stabilization fatty acid carboxylate than does Tyr-51 (kinetic parameters for laurate: R47A mutant, Km 859 µM, kcat 3960 min-1; Y51F 432 6140 wild-type, 288 5140 min-1). A slightly increased Y51F-catalysed is probably due...
An intronic G4C2 repeat expansion in the C9ORF72 gene is major known cause for Amyotrophic Lateral Sclerosis (ALS), with current evidence both, loss of function and pathological gain disease mechanisms. We screened 96 200 small molecules patient iPS neurons modulation nuclear RNA foci identified 82 validated hits, including Brd4 inhibitor JQ1 as well novel analogs Spliceostatin-A, a modulator SF3B1, branch point binding protein U2-snRNP. Spliceosome by these SF3B1 targeted compounds recruits...
The fact that war changes roles and responsibilities within society, while exposing men women of all ages classes to new threats opportunities, has become increasingly recognised. Civil wars disrupt destroy civilian life. Men leave, die in combat, are brutalised, lose employment, or resort despair, violence, apathy. Women assume enormous burdens work manner different tasks responsibilities, their security protectors, victimised marginalised. Yet few members peacekeeping missions have any...
Based on a boron-mediated syn aldol reaction of an alanine-derived ethyl ketone with α-chiral aldehyde partner, advanced intermediate for superstolide A was assembled in highly stereocontrolled fashion. Controlled 1,3-anti reduction the resulting β-hydroxy gave characteristic amino diol stereopentad superstolide, followed by Takai olefination and esterification C23 hydroxyl to provide elaborated C1-C5/C20-C26 segment 3.
The development of a scalable chiral synthesis for the HCV NS5B inhibitor MK-3281 is being reported. Several alternative routes were explored and are described.
Eine zweckdienliche Totalsynthese der Auriside A und B (1), außergewöhnlicher cytotoxischer Macrolidglycoside des japanischen Seehasen D. auricularia, nutzt für den stereokontrollierten Aufbau gemeinsamen Macrolidkerns eine hoch konvergente Aldolroute. Die Zuckereinheiten werden anschließend durch α-selektive Glycosylierung eingeführt. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2001/2005/z462267_s.pdf or from author. Please note:...
We describe the identification of a candidate positron emission tomography (PET) imaging agent for NLRP3 protein. plays critical role in immune system and has proven difficult target development agents due to its low cell-specific expression profile. A recently described series pyridazine-based inhibitors, with improved permeability brain-penetration properties, was used as starting point suitable PET agent. Optimization affinity, non-specific binding pharmacokinetic properties led...
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