A5079024504- Cytokine Signaling Pathways and Interactions
- Rheumatoid Arthritis Research and Therapies
- Protease and Inhibitor Mechanisms
- Synthesis and biological activity
- Chemical Synthesis and Analysis
- Psoriasis: Treatment and Pathogenesis
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Click Chemistry and Applications
- Peptidase Inhibition and Analysis
- Marine Sponges and Natural Products
- Asymmetric Synthesis and Catalysis
- Blood Coagulation and Thrombosis Mechanisms
- Carbohydrate Chemistry and Synthesis
- Traditional and Medicinal Uses of Annonaceae
- Chemical Synthesis and Reactions
- Oxidative Organic Chemistry Reactions
- Cell Adhesion Molecules Research
- Marine Toxins and Detection Methods
- Synthetic Organic Chemistry Methods
- Drug Transport and Resistance Mechanisms
- Tuberculosis Research and Epidemiology
- NF-κB Signaling Pathways
- Protein Kinase Regulation and GTPase Signaling
- Signaling Pathways in Disease
Bristol-Myers Squibb (United States)
2004-2020
Tianjin Medical University
2018
Bristol-Myers Squibb (Germany)
2002-2008
Experimental Station
1999-2003
Wilmington University
1999-2001
DuPont (United States)
1999-2000
University of Pennsylvania
1991-2000
Monell Chemical Senses Center
1991-1999
Philadelphia University
1993-1999
Harvard University
1993-1996
By addressing the relative stereochemistry of four acyclic portions via organic synthesis, complete maitotoxin (MTX) has been established as 1B. The C.1−C.15 portion was elucidated a two-phase approach: (1) synthesis eight diastereomers possible for model C, representing C.1−C.11 portion, and D, C.11−C.15 comparison their proton carbon NMR characteristics with those MTX, concluding that 9 35 represent corresponding MTX; (2) two remote 51 52, represents MTX. C.35−C.39, C.63−C.68, C.134−C.142 ...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTIodine monobromide (IBr) at low temperature: enhanced diastereoselectivity in electrophilic cyclizations of homoallylic carbonatesJames J. W. Duan and Amos B. Smith IIICite this: Org. Chem. 1993, 58, 14, 3703–3711Publication Date (Print):July 1, 1993Publication History Published online1 May 2002Published inissue 1 July 1993https://pubs.acs.org/doi/10.1021/jo00066a024https://doi.org/10.1021/jo00066a024research-articleACS PublicationsRequest reuse...
New γ-lactam TACE inhibitors were designed from known MMP inhibitors. A homology model of was built and examined to identify the S1' site as key area for selectivity over MMPs. Rational exploration P1'−S1' interactions resulted in discovery 3,5-disubstituted benzyl ether a TACE-selective P1' group. Further optimization led IK682 selective orally bioavailable inhibitor.
A new phenyl (3-phenylpyrrolidin-3-yl)sulfone series of RORγt inverse agonists was discovered utilizing the binding conformation previously reported bicyclic sulfonamide 1. Through a combination structure-based design and structure-activity relationship studies, polar set amides at N1-position pyrrolidine ring perfluoroisopropyl group para-position 3-phenyl were identified as critical structural elements to achieve high selectivity against PXR, LXRα, LXRβ. Further optimization led discovery...
Tumor necrosis factor alpha (TNFalpha) is an immunomodulatory and proinflammatory cytokine implicated in neuroinflammation neuronal damage response to cerebral ischemia. factor-alpha converting enzyme (TACE or ADAM17) a key sheddase that releases TNFalpha from its inactive cell-bound precursor. Using selective small molecule inhibitor of TACE, DPH-067517, we tested the hypothesis inhibition formation might have salutary effect ischemic stroke induced by embolic occlusion middle artery...
Novel tricyclic analogues were designed, synthesized, and evaluated as RORγt inverse agonists. Several of these compounds potent in an IL-17 human whole blood assay exhibited excellent oral bioavailability mouse pharmacokinetic studies. This led to the identification compound 5, which displayed dose-dependent inhibition IL-17F production a IL-2/IL-23 stimulated pharmacodynamic model. In addition, 5 was studied acanthosis imiquimod-induced models skin inflammation, where it demonstrated...
RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, has been identified potential target for treatment various immunological disorders psoriasis, psoriatic arthritis, inflammatory bowel diseases. Structure computer-assisted drug design led to identification novel series tricyclic inverse agonists with significantly improved in vitro activity reporter (Gal4) human whole blood assays compared our...
Abstract Microhomology-mediated end joining (MMEJ) is a repair mechanism that resolves double strand DNA breaks. It considered secondary break behind homologous recombination (HR) but often utilized by tumors have lost the ability to perform HR. Critical this process polymerase theta (Pol θ). Pol θ heterobifunctional protein consists of an N-terminal helicase domain, disorder central region and C-terminal domain. Following resection MRE11-RAD50-NBS-1 (MRN) complex recruited site where it...
To search for TNF-alpha (tumor necrosis factor alpha) converting enzyme (TACE) inhibitors, we designed a new class of macrocyclic hydroxamic acids by linking the P1 and P2' residues acyclic anti-succinate-based acids. A variety including amide, carbamate, alkyl, sulfonamido, Boc-amino, amino were found to be suitable P1-P2' linkers. With an N-methylamide at P3', 13-16-membered macrocycles prepared exhibited low micromolar activities in inhibition release from LPS-stimulated human whole...
An asymmetric synthesis of the stereochemically fully endowed C(9−25) spiroketal fragment (+)-BC calyculins (1−8) is described. Highlights include: a highly diastereoselective IBr-induced iodocarbonate cyclization to introduce C(21) stereocenter in epoxide (+)-18, unions exploiting reaction acyl anion equivalents with epoxides construct masked advanced aldols (−)-35 and (+)-71 as single diastereomers, chelation-controlled addition C(14−15) vinyl group aldehyde (+)-38 set stereogenicity at...
Scaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor alpha (TNFα). Structure–activity relationships in both the quinoline naphthyridine series leading identification compound 42 with excellent potency pharmacokinetic profile are discussed. X-ray co-crystal structure analysis ultracentrifugation experiments clearly demonstrate that these distort TNFα trimer...
A convergent total synthesis leading to (+)-calyculin and (−)-calyculin B (1 2), antipodes of the potent, highly selective remarkably cell-permeable phosphatase inhibitors calyculins B, has been achieved. In preceding paper we outlined asymmetric C(9−25) spiroketal dipropionate subunit (+)-BC; herein describe construction C(1−8) cyanotetraene, an C(26−37) oxazole, fragment assembly final elaboration (+)-1 (−)-2. Highlights include: application a one-pot three-component Suzuki reaction for...
Elevated levels of tumor necrosis factor-alpha (TNF-alpha) have been associated with several inflammatory diseases, and therefore, strategies for its suppression become important targets in drug discovery. Our efforts to suppress TNF-alpha centered on the inhibition converting enzyme (TACE) through use hydroxamate inhibitors. Starting from broad-spectrum matrix metalloproteinase (MMP) inhibitors, we designed synthesized novel benzothiadiazepines as potent selective TACE The were variation P1...
DPC 333 ((2<i>R</i>)-2-((3<i>R</i>)-3-amino-3{4-[2-methyl-4-quinolinyl) methoxy] phenyl}-2-oxopyrrolidinyl)-<i>N</i>-hydroxy-4-methylpentanamide)) is a potent and selective inhibitor of tumor necrosis factor (TNF)-α-converting enzyme (TACE). It significantly inhibits lipopolysaccharide-induced soluble TNF-α production in blood from rodents, chimpanzee, human, with IC<sub>50</sub> values ranging 17 to 100 nM. In rodent models endotoxemia, inhibited the dose-dependent manner, an oral...
purpose. The efficacy of three matrix metalloproteinase (MMP) inhibitors with various selectivities (Ro-31-9790, AG3340, and DPC-A37668) was investigated in a rat model retinopathy prematurity, to examine the roles MMP-2 -9 retinal neovascularization. susceptibilities MMP-2−/− -9−/− mice preretinal neovascularization were mouse oxygen-induced retinopathy. methods. Sprague-Dawley newborn rats exposed alternating episodes 50% 10% oxygen (variable exposure) induce Three MMP selectivity profiles...