A5025695028- Hepatitis C virus research
- HIV/AIDS drug development and treatment
- Asymmetric Synthesis and Catalysis
- Cancer-related gene regulation
- Biochemical and Molecular Research
- Hepatitis B Virus Studies
- Receptor Mechanisms and Signaling
- Ion channel regulation and function
- RNA Research and Splicing
- Synthesis and Biological Evaluation
- Liver Disease Diagnosis and Treatment
- Diabetes Treatment and Management
- Oxidative Organic Chemistry Reactions
- Cardiac Ischemia and Reperfusion
- Regulation of Appetite and Obesity
- Synthetic Organic Chemistry Methods
- Wnt/β-catenin signaling in development and cancer
- X-ray Diffraction in Crystallography
- Molecular spectroscopy and chirality
- Influenza Virus Research Studies
- Carbohydrate Chemistry and Synthesis
- Crystallography and molecular interactions
- Axial and Atropisomeric Chirality Synthesis
- Advanced Synthetic Organic Chemistry
- Synthesis and Reactions of Organic Compounds
South College
2019-2024
GlaxoSmithKline (United States)
2002-2019
Research Triangle Park Foundation
2002-2015
IIT@MIT
1995-2000
Massachusetts Institute of Technology
1996-1999
Miami University
1991-1993
1. Long chain fatty acids have recently been identified as agonists for the G protein-coupled receptors GPR40 and GPR120. Here, we present first description of GW9508, a small-molecule agonist acid In addition, also describe pharmacology GW1100, selective antagonist. These molecules were used to further investigate role in glucose-stimulated insulin secretion MIN6 mouse pancreatic beta-cell line. 2. GW9508 linoleic both stimulated intracellular Ca2+ mobilization human embryonic kidney...
DNA-encoded library (DEL) technology is a powerful tool commonly used by the pharmaceutical industry for identification of compounds with affinity to biomolecular targets. Success in this endeavor lies sampling diverse chemical libraries. However, current DELs tend be deficient C(sp3) carbon counts. We report unique solutions challenge increasing both diversity these libraries and their counts merging Ni/photoredox dual catalytic C(sp2)-C(sp3) cross-coupling as well photoredox-catalyzed...
Two novel routes involving the intramolecular olefin insertion with a zirconium−benzyne complex, followed by palladium-catalyzed aryl amination, have been developed for synthesis of tetrahydropyrroloquinolines. In one approach, exemplified in six-step total South American toad poison dehydrobufotenine (1), tricyclic system was formed via Pd-catalyzed ring closure functionalized tryptamine derivative. second, cyclization an appropriately substituted quinoline yields 13, intermediate damirones...
We previously described the discovery of GSK5852 (1), a non-nucleoside polymerase (NS5B) inhibitor hepatitis C virus (HCV), in which an N-benzyl boronic acid was essential for potent antiviral activity. Unfortunately, facile benzylic oxidation resulted short plasma half-life (5 h) human volunteers, and backup program initiated to remove metabolic liabilities associated with 1. Herein, we describe second-generation NS5B inhibitors including GSK8175 (49), sulfonamide- N-benzoxaborole analog...
A new series of non-nucleoside reverse transcriptase inhibitors based on an imidazole-amide biarylether scaffold has been identified and shown to possess potent antiviral activity against HIV-1, including the NNRTI-resistant Y188L mutated virus. X-ray crystallography bound transcriptase, a structure RT protein, was used extensively help identify optimize key hydrogen-bonding motif. This led directly design compound 43 that exhibits remarkable (EC50<1 nM) wide range viruses favorable...
A boronic acid moiety was found to be a critical pharmacophore for enhanced in vitro potency against wild-type hepatitis C replicons and known clinical polymorphic resistant HCV mutant replicons. The synthesis, optimization, structure-activity relationships associated with inhibition of replication subgenomic system series non-nucleoside boron-containing RNA-dependent RNA polymerase (NS5B) inhibitors are described. summary the discovery 3 (GSK5852), molecule which entered trials subjects...
A series of imidazo[1,2-a]pyridines which directly bind to HCV Non-Structural Protein 4B (NS4B) is described. This demonstrates potent in vitro inhibition replication (EC50 < 10 nM), direct binding purified NS4B protein (IC50 20 and an resistance pattern associated with (H94N/R, V105L/M, F98L) that are unique among reported clinical assets, suggestive the potential for additive or synergistic combination other small molecule inhibitors replication.
We describe the preclinical development and in vivo efficacy of a novel chemical series that inhibits hepatitis C virus replication via direct interaction with viral nonstructural protein 4B (NS4B). Significant potency improvements were realized through isosteric modifications to our initial lead 1a. The temptation improve antiviral activity while compromising physicochemical properties was tempered by judicial use ligand efficiency indices during optimization. In this manner, compound 1a...
Reporter viruses are useful probes for studying multiple stages of the viral life cycle. Here we describe an expanded toolbox fluorescent and bioluminescent influenza A reporter viruses. The enhanced utility these tools enabled kinetic studies attachment, infection, co-infection. Multi-modal bioluminescence positron emission tomography-computed tomography (PET/CT) imaging infected animals revealed that antiviral treatment reduced load, dissemination, inflammation. These new technologies...
A new approach for the construction of indoles employing air- and moisture-stable reagent Cp2TiCl2 is described. The key steps involved are (1) intermolecular insertion reactions an olefin a titanocene-stabilized benzyne complex (2) Pd-catalyzed aryl amination reaction. simplicity availability requisite starting materials give method broad scope preparation polysubstituted indoles.
Excessive neutrophil migration has been correlated with influenza symptom severity. Danirixin (GSK1325756), a selective and reversible antagonist of C-X-C chemokine receptor 2, decreases activation transmigration to areas inflammation. This study evaluated the efficacy safety intravenous (IV) danirixin co-administered oseltamivir for treatment adults hospitalized influenza.In this phase 2b, double-blind, 3-arm (NCT02927431), influenza-positive participants were randomized 2:2:1 receive 15mg...
To identify novel antivirals to the hepatitis C virus (HCV) NS4B protein, we utilized encoded library technology (ELT), which enables purified proteins not amenable standard biochemical screening methods be tested against large combinatorial libraries in a short period of time. We several DNA-encoded (DEL) and identified single DEL feature that was subsequently progressed off-DNA synthesis. The most active initial synthesized compounds had 50% inhibitory concentrations (IC50s) 50 130 nM...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSynthesis and Reactions of 3-(Bromomethyl)-1-carbethoxy-4-iodoindole: The Preparation 3,4-Differentially Substituted IndolesJeffrey H. Tidwell, Andrew J. Peat, Stephen L. BuchwaldCite this: Org. Chem. 1994, 59, 23, 7164–7168Publication Date (Print):November 1, 1994Publication History Published online1 May 2002Published inissue 1 November 1994https://pubs.acs.org/doi/10.1021/jo00102a055https://doi.org/10.1021/jo00102a055research-articleACS...
The high expression of MCH in the hypothalamus with lean hypophagic phenotype coupled increased resting metabolic rate and resistance to fat diet-induced obesity KO mice has spurred considerable efforts develop small molecule MCHR1 antagonists. Starting from a lead thienopyrimidinone series, structure-activity studies at 3- 6-positions core afforded potent selective antagonists representative examples having suitable pharmacokinetic properties. Based on relationships, structural model for...
In the aftermath of COVID-19 pandemic, opportunities to modulate biological pathways common lifecycles viruses need be carefully considered.
ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTA Combined Zirconocene Benzyne−Palladium Cross-Coupling Route to Substituted Biphenyls and TerphenylsMichael Frid, Dolores Pérez, Andrew J. Peat, Stephen L. BuchwaldView Author Information Department of Chemistry Massachusetts Institute Technology Cambridge, 02139 Cite this: Am. Chem. Soc. 1999, 121, 40, 9469–9470Publication Date (Web):September 24, 1999Publication History Received7 July 1999Published online24 September inissue 1 October...
Danirixin (DNX), a selective and reversible CXC chemokine receptor 2 antagonist, inhibits neutrophil transmigration activation. This study assessed the safety, tolerability, clinical effect of DNX with without oseltamivir (OSV) in adults acute, uncomplicated influenza.This was placebo-controlled, double-blind, Phase IIa study. Participants (18-64 years) influenza-like symptoms (onset ≤48 hours) positive influenza rapid antigen test were randomized 2:1:2:1 to DNX, placebo, DNX+OSV, or OSV (75...