A5064702968- HIV/AIDS drug development and treatment
- Hepatitis C virus research
- Monoclonal and Polyclonal Antibodies Research
- Carbohydrate Chemistry and Synthesis
- Glycosylation and Glycoproteins Research
- HIV Research and Treatment
- Chemical Synthesis and Analysis
- Hepatitis B Virus Studies
- Biochemical and Molecular Research
- Click Chemistry and Applications
- X-ray Diffraction in Crystallography
- HIV-related health complications and treatments
- Crystallization and Solubility Studies
- Peptidase Inhibition and Analysis
- Cytokine Signaling Pathways and Interactions
- Ovarian function and disorders
- DNA and Nucleic Acid Chemistry
- Computational Drug Discovery Methods
- Hypothalamic control of reproductive hormones
- Synthesis and Catalytic Reactions
- Drug Transport and Resistance Mechanisms
- Enzyme Production and Characterization
- RNA Research and Splicing
- Genetic Neurodegenerative Diseases
- Synthetic Organic Chemistry Methods
AbbVie (United States)
2014-2024
Abbott (United States)
2001-2012
Sterling Research Group
2010-2011
Abbott Fund
2004-2010
Sarepta Therapeutics (United States)
2004
Abbott (United Kingdom)
2001
Carnegie Mellon University
1997
Columbia University
1994-1997
Kettering University
1996
Yale University
1993-1994
Repeating glycosidic linkages of oligosaccharides can be synthesized by solid-phase methods. Glycals were attached to a polystyrene copolymer with silyl ether bond and activated function as glycosyl donors 3,3-dimethyldioxirane. Glycosidation was performed reactions solution-based acceptor (itself glycal). Excess promoter removed rinsing after each coupling, the desired then easily obtained from polymer addition tetra- n -butylammonium fluoride. By this method, glycosidations are...
Huntington's disease (HD) is a currently incurable neurodegenerative caused by the expansion of CAG trinucleotide repeat within huntingtin (HTT) gene. Therapeutic approaches include selectively inhibiting expression mutated HTT allele while conserving function normal allele. We have evaluated series antisense oligonucleotides (ASOs) targeted to expanded mRNA for their ability inhibit mutant protein. Several ASOs incorporating variety modifications, including bridged nucleic acids and...
Pibrentasvir (ABT-530) is a novel and pan-genotypic hepatitis C virus (HCV) NS5A inhibitor with 50% effective concentration (EC50) values ranging from 1.4 to 5.0 pM against HCV replicons containing genotypes 1 6. demonstrated similar activity panel of chimeric 6 clinical samples. Resistance selection studies were conducted using replicon cells genotype 1a, 1b, 2a, 2b, 3a, 4a, 5a, or 6a at pibrentasvir that was 10- 100-fold over its EC50 for the respective replicon. With 10-fold EC50, only...
We describe here N-phenylpyrrolidine-based inhibitors of HCV NS5A with excellent potency, metabolic stability, and pharmacokinetics. Compounds 2S,5S stereochemistry at the pyrrolidine ring provided improved genotype 1 (GT1) potency compared to 2R,5R analogues. Furthermore, attachment substituents 4-position central N-phenyl group resulted in compounds potency. Substitution tert-butyl, as compound 38 (ABT-267), low-picomolar EC50 values superior It was discovered that a pan-genotypic...
Compounds that inhibit glutathione peroxidase 4 (GPX4) hold promise as cancer therapeutics in their ability to induce a form of nonapoptotic cell death called ferroptosis. Our research identified 24, structural analog the potent GPX4 inhibitor RSL3, has much better plasma stability (t1/2 > 5 h mouse plasma). The bioavailability 24 provided efficacious drug concentrations with IP dosing, thus enabling vivo studies assess tolerability and efficacy. An efficacy study using GPX4-sensitive tumor...
BILN 2061 is a novel, specific hepatitis C virus (HCV) NS3 serine protease inhibitor discovered by Boehringer Ingelheim that has shown potent activity against HCV replicons in tissue culture and currently under clinical investigation for the treatment of infection. The poor fidelity RNA-dependent RNA polymerase will likely lead to development drug-resistant viruses treated patients. resistance was studied vitro passage genotype 1b replicon cells presence fixed concentration drug. Three weeks...
In this work, we studied the fluorescence and hybridization of multiply-labeled DNA probes which have hydrophilic fluorophore 1-(straightepsilon-carboxypentynyl)-1'-ethyl- 3,3,3', 3'-tetramethylindocarbocyanine-5,5'-disulfonate (Cy3) attached via either a short or long linker at C-5 position deoxyuridine. We describe effects labeling density, charge length upon five properties probe: intensity, change in duplex formation, quantum yield (Phif), probe-target stability specificity. For dye Cy3,...
Bacterial lipopolysaccharide (LPS), tumor necrosis factor (TNF)-a and interleukin-lp (IL-1p) stimulate similar cellular responses.TNF-a IL-1p are known to initiate signaling through a pathway involving hydrolysis of sphingomyelin ceramide (Kolesnick, R. N., Golde, D. W. (1994) Cell 77, 325428).In this system, acts as second messenger stimulating ceramide-activated serinelthreonine protein kinase.The present studies demonstrate that LPS, like TNF IL-1, stimulates kinase activity in human...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMajor Simplifications in Oligosaccharide Syntheses Arising from a Solid-Phase Based Method: An Application to the Synthesis of Lewis b AntigenJohn T. Randolph, Kim F. McClure, and Samuel J. DanishefskyCite this: Am. Chem. Soc. 1995, 117, 21, 5712–5719Publication Date (Print):May 1, 1995Publication History Published online1 May 2002Published inissue 1...
Using a convergent synthetic route to enable multiple points of diversity, series glucocorticoid receptor modulators (GRM) were profiled for potency, selectivity, and drug-like properties in vitro. Despite covering large range profiling the nonconjugated small molecule was suboptimal they conjugated mouse antitumor necrosis factor (TNF) antibody using MP-Ala-Ala linker. Screening resulting drug conjugates (ADCs) provided better assessment efficacy physical properties, reinforcing need...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTTotal Synthesis of a Human Breast Tumor Associated AntigenMark T. Bilodeau, Tae Kyo Park, Shuanghua Hu, John Randolph, Samuel J. Danishefsky, Philip O. Livingston, and Shengli ZhangCite this: Am. Chem. Soc. 1995, 117, 29, 7840–7841Publication Date (Print):July 1, 1995Publication History Published online1 May 2002Published inissue 1 July 1995https://pubs.acs.org/doi/10.1021/ja00134a043https://doi.org/10.1021/ja00134a043research-articleACS...
The total synthesis of the Hakomori MBr1 antigen, heavily expressed on human breast tumors, is related. construction involved assembly four glycals: (17 (twice), 18, 20, and 26) an l-fucose derivative, 34. sensitivity stereochemistry sulfonamido galactosylation by a terminal galactose ring as function state protection status its C4 alcohol was exploited in key step. (See formation compound 51.) served to confirm assignment structure, paves way for immunoconjugation. 64.)
Curative interferon and ribavirin sparing treatments for hepatitis C virus (HCV)-infected patients require a combination of mechanistically orthogonal direct acting antivirals. A shared component these is usually an HCV NS5A inhibitor. First generation FDA approved treatments, including the inhibitors, do not exhibit equivalent efficacy against genotypes 1–6. In particular, first inhibitors tend to select viral drug resistance. Ombitasvir inhibitor included as key Viekira Pak treatment with...
Spinocerebellar ataxia-3 (also known as Machado-Joseph disease) is an incurable neurodegenerative disorder caused by expression of a mutant variant ataxin-3 (ATX3) protein. Inhibiting ATX3 would provide therapeutic strategy, but indiscriminant inhibition both wild-type and might lead to undesirable side effects. An ideal silencing agent block while leaving intact. We have previously observed that peptide nucleic acid (PNA) conjugates targeting the expanded CAG repeat within mRNA alleles. now...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTApplication of the Glycal Assembly Method to Concise Synthesis Neoglycoconjugates Ley and Leb Blood Group Determinants H-Type I II OligosaccharidesSamuel J. Danishefsky, Victor Behar, John T. Randolph, Kenneth O. LloydCite this: Am. Chem. Soc. 1995, 117, 21, 5701–5711Publication Date (Print):May 1, 1995Publication History Published online1 May 2002Published inissue 1...
Minimal use of protecting groups is required in the synthesis branched hexa-saccharide Lewisb 1. Thus, donor and acceptor glycosyl units were linked stereo-selectively to polymer-bound glycal such a way that an oligosaccharide recognition element formed which can be bound carrier protein.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTFirst Synthesis of a Digitalis Saponin. Demonstration the Scope and Limitations Convergent Scheme for Branched Oligosaccharide by Logic Glycal AssemblyJohn T. Randolph Samuel J. DanishefskyCite this: Am. Chem. Soc. 1995, 117, 21, 5693–5700Publication Date (Print):May 1, 1995Publication History Published online1 May 2002Published inissue 1 1995https://pubs.acs.org/doi/10.1021/ja00126a010https://doi.org/10.1021/ja00126a010research-articleACS...
Inhibitors of hepatitis C virus (HCV) protease have shown marked antiviral activity in short-term clinical studies HCV-infected individuals. The interaction the investigational HCV inhibitors VX-950 and SCH 503034 with ritonavir, a potent inhibitor cytochrome P450 3A, was studied vitro vivo. In rat human liver microsomes, metabolism strongly inhibited by presence 4 microM ritonavir. Upon co-dosing either or ritonavir rats, plasma exposure increased > 15-fold, concentrations 8 h after dosing...
Benzothiadiazine inhibitors of the HCV NS5B RNA-dependent RNA polymerase are an important class non-nucleoside that have received considerable attention in search for novel therapeutics. Research our laboratories has identified a series tetracyclic benzothiadiazine bearing benzylamino substituent on B-ring. Compounds this exhibit low-nanomolar activities both genotypes 1a and 1b inhibition assays subgenomic replicon assays. Optimization pharmacokinetic properties rat led to compound 30,...
We describe the discovery of a thioester-containing glucocorticoid receptor modulator (GRM) payload and corresponding antibody-drug conjugate (ADC). Payload
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTApplication of the glycal assembly strategy to synthesis a branched oligosaccharide: first complex saponinJohn T. Randolph and Samuel J. DanishefskyCite this: Am. Chem. Soc. 1993, 115, 18, 8473–8474Publication Date (Print):September 1, 1993Publication History Published online1 May 2002Published inissue 1 September 1993https://pubs.acs.org/doi/10.1021/ja00071a077https://doi.org/10.1021/ja00071a077research-articleACS PublicationsRequest reuse...
A series of symmetry-based HIV protease inhibitors was designed and synthesized. Modification the core regiochemistry stereochemistry significantly affected potency, metabolic stability, oral bioavailability inhibitors, as did variation a pendent arylmethyl P3 group. Optimization led to selection two compounds, 10c (A-790742) 9d (A-792611), for advancement preclinical studies. Both compounds displayed low nanomolar potency against wild type in presence human serum, rates metabolism liver...