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Wensheng Yu, Ling Tong, Oleg Selyutin, Lei Chen, Bin Hu, Bin Zhong, Jinglai Hao, Tao Ji, Shuai Zan, Jingjun Yin, Rebecca Tamra Ruck, Stephanie Curry, Patricia McMonagle, Sony Agrawal, Laura Rokosz, Donna Carr, Paul Ingravallo, Karin Bystol, Frederick Lahser, Rong Liu, Shiying Chen, Kung-I Feng, Mark Cartwright, Ernest Asante-Appiah, Joseph A Kozlowski
We describe the discovery of MK-6169, a potent and pan-genotype HCV NS5A inhibitor with optimized activity against common resistance-associated substitutions. SAR studies around the combination of changes to both the valine and aminal carbon region of elbasvir lead to the discovery of a series of compounds with substantially improved potency against common resistance-associated substitutions in the major genotypes, as well as good pharmacokinetics in both rat and dog. Through further optimization of key leads from this effort, MK-6169 (21) was discovered as a pre-clinical candidate for further development...
April 21, 2018: Journal of Medicinal Chemistry
Ling Tong, Wensheng Yu, Lei Chen, Oleg Selyutin, Michael P Dwyer, Anilkumar G Nair, Robert Mazzola, Jae-Hun Kim, Deyou Sha, Jingjun Yin, Rebecca T Ruck, Ian W Davies, Bin Hu, Bin Zhong, Jinglai Hao, Tao Ji, Shuai Zan, Rong Liu, Sony Agrawal, Ellen Xia, Stephanie Curry, Patricia McMonagle, Karin Bystol, Frederick Lahser, Donna Carr, Laura Rokosz, Paul Ingravallo, Shiying Chen, Kung-I Feng, Mark Cartwright, Ernest Asante-Appiah, Joseph A Kozlowski
We describe the research that led to the discovery of compound 40 (ruzasvir, MK-8408), a pan-genotypic HCV nonstructural protein 5A (NS5A) inhibitor with a "flat" GT1 mutant profile. This NS5A inhibitor contains a unique tetracyclic indole core while maintaining the imidazole-proline-valine Moc motifs of our previous NS5A inhibitors. Compound 40 is currently in early clinical trials and is under evaluation as part of an all-oral DAA regimen for the treatment of chronic HCV infection.
January 12, 2017: Journal of Medicinal Chemistry
Ling Tong, Wensheng Yu, Craig A Coburn, Lei Chen, Oleg Selyutin, Qingbei Zeng, Michael P Dwyer, Anilkumar G Nair, Bandarpalle B Shankar, Seong Heon Kim, De-Yi Yang, Stuart B Rosenblum, Rebecca T Ruck, Ian W Davies, Bin Hu, Bin Zhong, Jinglai Hao, Tao Ji, Shuai Zan, Rong Liu, Sony Agrawal, Donna Carr, Stephanie Curry, Patricia McMonagle, Karin Bystol, Frederick Lahser, Paul Ingravallo, Shiying Chen, Ernest Asante-Appiah, Joseph A Kozlowski
We describe the impact of proline modifications, in our tetracyclic-indole based series of nonstructural protein 5A (NS5A) inhibitors, to their replicon profiles. This work identified NS5A inhibitors with an improved and flattened resistance profiles.
November 1, 2016: Bioorganic & Medicinal Chemistry Letters
Frederick C Lahser, Karin Bystol, Stephanie Curry, Patricia McMonagle, Ellen Xia, Paul Ingravallo, Robert Chase, Rong Liu, Todd Black, Daria Hazuda, Anita Y M Howe, Ernest Asante-Appiah
The selection of resistance-associated variants (RAVs) against single agents administered to patients chronically infected with hepatitis C virus (HCV) necessitates that direct-acting antiviral agents (DAAs) targeting multiple viral proteins be developed to overcome failure resulting from emergence of resistance. The combination of grazoprevir (formerly MK-5172), an NS3/4A protease inhibitor, and elbasvir (formerly MK-8742), an NS5A inhibitor, was therefore studied in genotype 1a (GT1a) replicon cells. Both compounds were independently highly potent in GT1a wild-type replicon cells, with 90% effective concentration (EC90) values of 0...
May 2016: Antimicrobial Agents and Chemotherapy
Colleen N Kristensen, Karin M Bystol, Boran Li, Lourdes Serrano, Mark A Brenneman
DSS1 is a small, highly acidic protein widely conserved among eukaryotes as a component of the 19S proteasome and implicated in ubiquitin-mediated proteolysis. The BRCA2 tumor suppressor protein functions in homologous recombinational repair (HRR) of DNA double-strand breaks, and does so in part through the actions of a carboxy-proximal region that binds DNA and several other proteins, including DSS1. In the unicellular eukaryote Ustilago maydis, Dss1 interacts with Brh2, a BRCA2-like protein, and regulates its function in mediating HRR...
December 10, 2010: Mutation Research
Olga Hilas, Danielle Ezzo
No abstract text is available yet for this article.
April 2009: P & T: a Peer-reviewed Journal for Formulary Management
S Mathkar, S Kumar, A Bystol, K Olawoore, D Min, R Markovich, A Rustum
Reference standards are routinely used in pharmaceutical industry to determine strength, content, and the quality of drug products, active pharmaceutical ingredients (API), preservatives, antioxidants and excipients. Traditionally, chromatographic techniques such as High Performance Liquid Chromatography (HPLC) and Gas Chromatography (GC) in conjunction with other analytical techniques have been used to determine the purity and strength of a specific lot of a compound for the purpose of qualifying the lot to use as a reference standard...
April 5, 2009: Journal of Pharmaceutical and Biomedical Analysis
Gary Laustsen, Fernando Carrillo, Jessica Johnson, Cynthia Smith
No abstract text is available yet for this article.
February 2009: Nurse Practitioner
Joe Strain, Lindsey Brown
No abstract text is available yet for this article.
June 2008: South Dakota Medicine: the Journal of the South Dakota State Medical Association
Adam J Bystol, Shenjiang Yu, Andres D Campiglia
Laser-excited time-resolved Shpol'skii spectrometry at liquid helium temperature (4.2 K) is presented for the analysis of polycyclic aromatic hydrocarbons in high-performance liquid chromatography fractions. Fluorescence measurements are rapidly done with the aid of a fiber-optic probe, pulsed tunable dye laser, spectrograph, and intensified charge-coupled device. Analyte identification and peak-purity checking are made through wavelength-time matrix formats, which give simultaneous access to spectral and lifetime information...
June 13, 2003: Talanta
Adam J Bystol, Jennifer L Whitcomb, Andres D Campiglia
A new procedure is presented for the analysis of polycyclic aromatic hydrocarbons by solid-liquid extraction (SLE) and laser-excited time-resolved Shpol'skii spectrometry (LETRSS). Microliters of Shpol'skii solvent are spiked on the surface of the extraction membrane and LETRSS is directly performed on the organic layer above the surface of the solid substrate. Fluorescence measurements are easily performed with a fiber-optic cell specifically designed for cryogenic measurements at 77 and 4.2 K. In comparison to the SLE-LETRSS procedure previously reported (Environ...
July 19, 2002: Talanta
Sandeep Gupta, Harold M Wright
Nebivolol (Bystolic) is a cardioselective beta 1 (beta(1))-adrenergic receptor blocker with endothelium-dependent vasodilating properties. The endothelium-dependent relaxation induced by nebivolol is blocked by inhibitors of nitric oxide synthase (NOS) and guanylate cyclase. Nebivolol also increases in vitro and in vivo nitric oxide (NO), which is an essential signaling molecule involved in the maintenance of cardiovascular homeostasis. This review summarizes the data involving nebivolol and NO bioavailability...
2008: Cardiovascular Therapeutics
David Wojciechowski, Vasilios Papademetriou
Hypertension is a major cardiovascular risk factor but most patients remain asymptomatic for many years. Successful therapy not only needs to be effective, it also needs to be well tolerated. beta-blockers are well established as effective antihypertensive agents. However, one major drawback to the currently available beta-blockers, particularly the noncardioselective beta-blockers, is their side-effect profile, including sexual dysfunction, fatigue, depression and metabolic abnormalities such as impaired glucose tolerance and lipid abnormalities...
April 2008: Expert Review of Cardiovascular Therapy
(no author information available yet)
No abstract text is available yet for this article.
March 10, 2008: Medical Letter on Drugs and Therapeutics
Andres D Campiglia, Shenjiang Yu, Adam J Bystol, Huiyong Wang
Recording absorption spectra via transmittance through frozen matrixes is a challenging task. The main reason is the difficulty in overcoming the strong scattering light reaching the detector. This is particularly true when thick samples are necessary for recording absorption spectra of weak oscillators. In the case of strongly fluorescent compounds, additional errors in absorbance measurements arise from the emission reaching the detector, which might have an intensity comparable to that of the transmitted light...
February 15, 2007: Analytical Chemistry
Andres D Campiglia, Adam J Bystol, Shenjiang Yu
We present a single instrument with the capability to collect multidimensional data formats in both the fluorescence and the phosphorescence time domains. We also demonstrate the ability to perform luminescence measurements in highly scattering media by comparing the precision of measurements in Shpol'skii solvents to those obtained in "snowlike" matrixes and solid samples. For decades, conventional low-temperature methodology has been restricted to optically transparent media. This restriction has limited its application to organic solvents that freeze into a glass...
January 15, 2006: Analytical Chemistry
Adam J Bystol, Andres D Campiglia
The potential of solid-liquid extraction fluorescence line narrowing spectroscopy is evaluated for screening polycyclic aromatic hydrocarbons in aqueous samples. Octadecyl silica membranes are used with the dual purpose of sample preconcentration and solid substrate for spectroscopic measurements. 4.2 K fluorescence line narrowed spectra are directly recorded from the membrane with the aid of a fiber-optic probe. The experimental procedure is free from organic solvents and takes less than 5 min per sample. With 10 mL of water sample, the limits of detection are at the parts-per-billion level...
June 2003: Applied Spectroscopy
Adam J Bystol, Tim Thorstenson, Andres D Campiglia
Fluorescence measurements are easily made with the aid of a cryogenic fiber optic probe. Emission wavelength time matrixes, excitation emission matrixes, and time-resolved excitation emission matrixes are rapidly collected with a pulsed tunable dye laser, a spectrograph, and an intensified charged-coupled device. Compound identification is based on spectral and lifetime information. The potential of this approach for supporting high-performance liquid chromatography analysis and for the direct determination of benzo[a]pyrene without previous separation is demonstrated...
October 15, 2002: Environmental Science & Technology
A J Bystol, A D Campiglia, G D Gillispie
Improved methodology for chemical analysis via laser-excited Shpol'skii spectrometry at liquid helium temperature (4.2 K) is reported. Sample freezing is performed in a matter of seconds with the aid of a fiber-optic probe directly inserted into the liquid cryogen. Emission wavelength time matrixes, excitation emission wavelengths, and time-resolved excitation emission wavelengths are rapidly collected with the aid of a pulsed tunable dye laser, a high-resolution spectrograph, and an intensified charged-couple device...
December 1, 2001: Analytical Chemistry
A J Bystol, J L Whitcomb, A D Campiglia
A unique method for monitoring polycyclic aromatic hydrocarbons is reported for routine analysis of water samples. The assay consists of a three-step procedure. One hundred milliliters of water is processed through an octadecyl extraction membrane via solid-liquid extraction. The pollutants are eluted with 5 mL of n-hexane and directly determined in the eluting solvent by laser excited time-resolved Shpol'skii spectrometry. Seventy-seven K fluorescence measurements are made with the aid of an optical fiber probe that avoids the complications of classical low-temperature methodology...
June 15, 2001: Environmental Science & Technology
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