A5016374752- Chemical Synthesis and Analysis
- Advanced biosensing and bioanalysis techniques
- Click Chemistry and Applications
- Cytokine Signaling Pathways and Interactions
- Radical Photochemical Reactions
- Antibiotic Resistance in Bacteria
- DNA and Nucleic Acid Chemistry
- Synthesis and Biological Evaluation
- Rheumatoid Arthritis Research and Therapies
- Monoclonal and Polyclonal Antibodies Research
- Pharmacological Effects of Natural Compounds
- RNA and protein synthesis mechanisms
- Bioactive Compounds and Antitumor Agents
- Sulfur-Based Synthesis Techniques
- Bacterial Genetics and Biotechnology
- Synthesis and Catalytic Reactions
- Antibiotics Pharmacokinetics and Efficacy
- Synthesis and Biological Activity
- Catalytic C–H Functionalization Methods
- Innovative Microfluidic and Catalytic Techniques Innovation
- Oxidative Organic Chemistry Reactions
- Glycosylation and Glycoproteins Research
- Antimicrobial Peptides and Activities
- X-ray Diffraction in Crystallography
- Myeloproliferative Neoplasms: Diagnosis and Treatment
Pfizer (United States)
2014-2024
Foton Motors (China)
2016
Indiana University – Purdue University Indianapolis
2009-2013
Indiana University Health
2013
Regenstrief Institute
2009
Richard L. Roudebush VA Medical Center
2009
Stanford University
2003
Colorado State University
1991-2003
Howard Hughes Medical Institute
1996-1998
University of California, Berkeley
1996-1998
Because of its requirement for signaling by multiple cytokines, Janus kinase 3 (JAK3) is an excellent target clinical immunosuppression. We report the development a specific, orally active inhibitor JAK3, CP-690,550, that significantly prolonged survival in murine model heart transplantation and cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associated with hypertension, hyperlipidemia, or lymphoproliferative disease. On basis these preclinical results, we...
There is a critical need for safer and more convenient treatments organ transplant rejection autoimmune disorders such as rheumatoid arthritis. Janus tyrosine kinases (JAK1, JAK3) are expressed in lymphoid cells involved the signaling of multiple cytokines important various T cell functions. Blockade JAK1/JAK3-STAT pathway with small molecule was anticipated to provide therapeutic immunosuppression/immunomodulation. The Pfizer compound library screened against catalytic domain JAK3 resulting...
Interest in drugs that covalently modify their target is driven by the desire for enhanced efficacy can result from silencing of enzymatic activity until protein resynthesis occur, along with potential increased selectivity targeting uniquely positioned nucleophilic residues protein. However, covalent approaches carry additional risk toxicities or hypersensitivity reactions modification unintended targets. Here we describe methods measuring reactivity reactive groups (CRGs) a biologically...
Janus kinases (JAKs) are intracellular tyrosine that mediate the signaling of numerous cytokines and growth factors involved in regulation immunity, inflammation, hematopoiesis. As JAK1 pairs with JAK2, JAK3, TYK2, a JAK1-selective inhibitor would be expected to inhibit many inflammation immune function while avoiding inhibition JAK2 homodimer regulating erythropoietin thrombopoietin signaling. Our efforts began tofacitinib, an oral JAK approved for treatment rheumatoid arthritis. Through...
DNA Encoded Libraries have proven immensely powerful tools for lead identification. The ability to screen billions of compounds at once has spurred increasing interest in DEL development and utilization. Although provides access libraries unprecedented size diversity, the idiosyncratic hydrophilic nature tag severely limits scope applicable chemistries. It is known that biomacromolecules can be reversibly, noncovalently adsorbed eluted from solid supports, this phenomenon been utilized...
A new procedure for the photoredox-mediated conjugate addition of radicals that can be conveniently generated from α-amino acids to DNA-tagged Michael acceptors and styrenes is presented. This C(sp3 )-C(sp3 ) coupling tolerates a broad array structurally diverse radical precursors, including all 20 proteinogenic amino acids. Importantly, this reaction proceeds under mild conditions in DNA-compatible aqueous media. Furthermore, presented are compatible with DNA, making platform well suited...
A new catalytic manifold that merges photoredox with nickel catalysis in aqueous solution is presented. Specifically, the combination of a highly active, yet air-stable, precatalyst electron-deficient pyridyl carboxamidine ligand was key to development water-compatible platform, which crucial requirement for preparation DNA-encoded libraries (DELs). Together an iridium-based photocatalyst and powerful light source, this dual approach enabled efficient decarboxylative arylation α-amino acids...
Healthcare professionals develop workarounds rather than using electronic health record (EHR) systems. Understanding the reasons for is important to facilitate user-centered design and alignment between work context available information technology tools.To examine both paper- computer-based use of EHR systems in three benchmark institutions.Qualitative data were collected 11 primary care outpatient clinics across healthcare institutions. Data collection methods included direct observation...
High-throughput experimentation (HTE) has emerged as an important tool in drug discovery, providing a platform for preparing large compound libraries and enabling swift reaction screening over wide-ranging conditions. Recent advances automated high-density, material-sparing HTE have necessitated the development of rapid analytics with sensitivity resolution sufficient to identify products and/or assess performance timely data-rich manner. Combination ultrathroughput (UT) reader Acoustic...
DNA-compatible C(sp<sup>3</sup>)–H activation reactions of aliphatic carboxylic acids, amides, and ketones were developed for efficient access to DEL synthesis.
DNA encoded libraries (DEL) have shown promise as a valuable technology for democratizing the hit discovery process. Although DEL provides relatively inexpensive access to of unprecedented size, their production has been hampered by idiosyncratic needs encoding tag relegating compatible chemistry dilute aqueous environments. Recently reversible adsorption solid support (RASS) demonstrated promising method expand reactivity using standard organic synthesis protocols. Here we demonstrate suite...
The on-DNA synthesis of highly substituted cyclobutanes was achieved through a photocatalytic [2 + 2] cycloaddition reaction in aqueous solution. Readily available DNA-tagged styrene derivatives were reacted with structurally diverse cinnamates the presence an iridium-based photocatalyst, Ir(ppy)2(dtbbpy)PF6, to forge two new C(sp3)-C(sp3) bonds. This transformation demonstrated have excellent functional group tolerance and allowed for facile installation variety heteroaromatic substituents...
OBJECTIVE To facilitate patient handoffs between physicians, the computerized handoff tool (PHT) extracts information from electronic health record to populate a form that is printed and given cross-cover physician. OBJECTIVES were to: (1) evaluate rate at which data elements of interest extracted into PHT, (2) assess frequency for needing beyond contained in PHT where obtained, (3) physician's perceptions (4) identify opportunities improvement. DESIGN Observational study. MEASUREMENTS This...
A novel series of monocarbam compounds exhibiting promising antibacterial activity against multidrug resistant Gram-negative microorganisms is reported, along with the synthesis one such molecule MC-1 (1). Also reported are structure-activity relationships associated in vitro and vivo efficacy 1 related analogues addition to hydrolytic stability possible implications thereof.
Covalent drugs contain a reactive electrophilic moiety or covalent group (CRG), which forms an irreversible bond between the drug and biological target.
DNA-encoded chemical library (DECL) synthesis must occur in aqueous media under conditions that preserve the integrity of DNA encoding tag. While identification "DNA-compatible" reaction is critical for development DECL designs explore previously inaccessible space, reports measuring such compatibility have been largely restricted to methods do not faithfully capture impact on fidelity solution phase. Here we report a comprehensive methodology uses soluble substrates exactly recapitulate...
Over the past 20 years, toolbox for discovering small-molecule therapeutic starting points has expanded considerably. Pharmaceutical researchers can now choose from technologies that, in addition to traditional high-throughput knowledge-based and diversity screening, include screening of fragment fragment-like libraries, affinity selection mass spectrometry, against DNA-encoded libraries (DELs). Each these techniques its own unique combination advantages limitations that makes them more, or...
We report novel polymyxin analogues with improved antibacterial in vitro potency against resistant recent clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa . In addition, a human renal cell assay (hRPTEC) was used to inform structure-toxicity relationships further differentiate analogues. Replacement the Dab-3 residue Dap-3 combination relatively polar 6-oxo-1-phenyl-1,6-dihydropyridine-3-carbonyl side chain as fatty acyl replacement yielded analogue 5x, which...
Antibacterial compounds that affect bacterial viability have traditionally been identified, confirmed, and characterized in standard laboratory media. The historical success of identifying new antibiotics via this route has justifiably established a traditional means screening for antimicrobials. emergence multi-drug-resistant (MDR) pathogens expedited the need antibiotics, though many industry questioned source(s) these compounds. As pharmaceutical companies' chemical libraries exhaustively...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTCannizzaro-based O2-dependent cleavage of DNA by quinocarcinRobert M. Williams, Tomasz Glinka, Mark E. Flanagan, Renee Gallegos, Hazel Coffman, and Deihua PeiCite this: J. Am. Chem. Soc. 1992, 114, 2, 733–740Publication Date (Print):January 1, 1992Publication History Published online1 May 2002Published inissue 1 January 1992https://doi.org/10.1021/ja00028a049RIGHTS & PERMISSIONSArticle Views301Altmetric-Citations50LEARN ABOUT THESE METRICSArticle...
Respiratory tract bacterial strains are becoming increasingly resistant to currently marketed macrolide antibiotics. The current alternative telithromycin (1) from the newer ketolide class of macrolides addresses resistance but is hampered by serious safety concerns, hepatotoxicity in particular. We have discovered a novel series azetidinyl ketolides that focus on mitigation minimizing hepatic turnover and time-dependent inactivation CYP3A isoforms liver without compromising potency efficacy 1.