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Your search keyword '"Li, Lian‐Sheng"' showing total 5 results
Start Over Author "Li, Lian‐Sheng" Topic antiviral agents
5 results on '"Li, Lian‐Sheng"'

1. 5,5'- and 6,6'-dialkyl-5,6-dihydro-1H-pyridin-2-ones as potent inhibitors of HCV NS5B polymerase.

Author

Ellis DA, Blazel JK, Tran CV, Ruebsam F, Murphy DE, Li LS, Zhao J, Zhou Y, McGuire HM, Xiang AX, Webber SE, Zhao Q, Han Q, Kissinger CR, Lardy M, Gobbi A, Showalter RE, Shah AM, Tsan M, Patel RA, LeBrun LA, Kamran R, Bartkowski DM, Nolan TG, Norris DA, Sergeeva MV, and Kirkovsky L

Subjects
Animals, Antiviral Agents chemical synthesis, Antiviral Agents pharmacology, Binding Sites, Crystallography, X-Ray, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Humans, Macaca fascicularis, Microsomes, Liver metabolism, Pyridones chemical synthesis, Pyridones pharmacology, RNA-Dependent RNA Polymerase metabolism, Structure-Activity Relationship, Antiviral Agents chemistry, Enzyme Inhibitors chemistry, Hepacivirus enzymology, Pyridones chemistry, RNA-Dependent RNA Polymerase antagonists & inhibitors, Viral Nonstructural Proteins metabolism
Abstract

The discovery of 5,5'- and 6,6'-dialkyl-5,6-dihydro-1H-pyridin-2-ones as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC50 <0.10 microM). In vitro DMPK data for selected compounds as well as crystal structures of representative inhibitors complexed with the NS5B protein are also disclosed.

Published
2009
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2. Novel HCV NS5B polymerase inhibitors derived from 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones. Part 5: Exploration of pyridazinones containing 6-amino-substituents.

Author

Dragovich PS, Blazel JK, Ellis DA, Han Q, Kamran R, Kissinger CR, LeBrun LA, Li LS, Murphy DE, Noble M, Patel RA, Ruebsam F, Sergeeva MV, Shah AM, Showalter RE, Tran CV, Tsan M, Webber SE, Kirkovsky L, and Zhou Y

Subjects
Antiviral Agents pharmacology, Caco-2 Cells, Crystallography, X-Ray methods, Cyclic S-Oxides pharmacology, DNA-Directed RNA Polymerases chemistry, Drug Design, Genotype, Humans, Inhibitory Concentration 50, Microsomes metabolism, Models, Chemical, Molecular Conformation, Pyridazines pharmacology, Structure-Activity Relationship, Thiadiazines pharmacology, Antiviral Agents chemical synthesis, Chemistry, Pharmaceutical methods, Cyclic S-Oxides chemical synthesis, Pyridazines chemical synthesis, Pyridazines chemistry, Thiadiazines chemical synthesis, Viral Nonstructural Proteins antagonists & inhibitors, Viral Nonstructural Proteins chemistry
Abstract

The synthesis of 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones bearing 6-amino substituents as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC(50)<0.10 microM). In vitro DMPK data (microsome t(1/2), Caco-2 P(app)) for many of the compounds are also disclosed, and a crystal structure of a representative inhibitor complexed with the NS5B protein is discussed.

Published
2008
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3. Pyrrolo[1,2-b]pyridazin-2-ones as potent inhibitors of HCV NS5B polymerase.

Author

Ruebsam F, Webber SE, Tran MT, Tran CV, Murphy DE, Zhao J, Dragovich PS, Kim SH, Li LS, Zhou Y, Han Q, Kissinger CR, Showalter RE, Lardy M, Shah AM, Tsan M, Patel R, Lebrun LA, Kamran R, Sergeeva MV, Bartkowski DM, Nolan TG, Norris DA, and Kirkovsky L

Subjects
Animals, Antiviral Agents chemical synthesis, Antiviral Agents chemistry, Binding Sites drug effects, Cell Line, Crystallography, X-Ray, Humans, Hydrogen Bonding, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Pyridazines chemical synthesis, Pyridazines chemistry, Pyrroles chemical synthesis, Pyrroles chemistry, Structure-Activity Relationship, Viral Nonstructural Proteins chemistry, Antiviral Agents pharmacology, Pyridazines pharmacology, Pyrroles pharmacology, Viral Nonstructural Proteins antagonists & inhibitors
Abstract

Pyrrolo[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Structure-based design led to the discovery of compound 3 k, which displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; EC(50) (1b)=12 nM) as well as good stability towards human liver microsomes (HLM t(1/2)>60 min).

Published
2008
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4. Novel HCV NS5B polymerase inhibitors derived from 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones. Part 3: Further optimization of the 2-, 6-, and 7'-substituents and initial pharmacokinetic assessments.

Author

Li LS, Zhou Y, Murphy DE, Stankovic N, Zhao J, Dragovich PS, Bertolini T, Sun Z, Ayida B, Tran CV, Ruebsam F, Webber SE, Shah AM, Tsan M, Showalter RE, Patel R, Lebrun LA, Bartkowski DM, Nolan TG, Norris DA, Kamran R, Brooks J, Sergeeva MV, Kirkovsky L, Zhao Q, and Kissinger CR

Subjects
Administration, Oral, Animals, Antiviral Agents blood, Antiviral Agents chemistry, Combinatorial Chemistry Techniques, Drug Design, Humans, Microsomes, Liver drug effects, Molecular Structure, Pyridazines blood, Pyridazines chemistry, Rats, Structure-Activity Relationship, Antiviral Agents chemical synthesis, Antiviral Agents pharmacokinetics, Hepacivirus drug effects, Pyridazines chemical synthesis, Pyridazines pharmacokinetics, RNA-Dependent RNA Polymerase antagonists & inhibitors, Viral Nonstructural Proteins antagonists & inhibitors
Abstract

5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. Lead optimization led to the discovery of compound 3a, which displayed potent inhibitory activities in biochemical and replicon assays [IC(50) (1b)<10nM; IC(50) (1a)=22 nM; EC(50) (1b)=5nM], good stability toward human liver microsomes (HLM t(1/2)>60 min), and high ratios of liver to plasma concentrations 12h after a single oral administration to rats.

Published
2008
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5. Novel HCV NS5B polymerase inhibitors derived from 4-(1',1'-dioxo-1',4'-dihydro-1'lambda6-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones: Part 4. Optimization of DMPK properties.

Author

Sergeeva MV, Zhou Y, Bartkowski DM, Nolan TG, Norris DA, Okamoto E, Kirkovsky L, Kamran R, Lebrun LA, Tsan M, Patel R, Shah AM, Lardy M, Gobbi A, Li LS, Zhao J, Bertolini T, Stankovic N, Sun Z, Murphy DE, Webber SE, and Dragovich PS

Subjects
Administration, Oral, Animals, Antiviral Agents chemistry, Combinatorial Chemistry Techniques, Drug Design, Haplorhini, Inhibitory Concentration 50, Models, Molecular, Molecular Structure, Pyridazines chemistry, Structure-Activity Relationship, Antiviral Agents chemical synthesis, Antiviral Agents pharmacokinetics, Hepacivirus enzymology, Pyridazines chemical synthesis, Pyridazines pharmacokinetics, Viral Nonstructural Proteins antagonists & inhibitors
Abstract

5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as potent inhibitors of genotype 1 HCV NS5B polymerase focusing on the optimization of their drug metabolism and pharmacokinetics (DMPK) profiles. This investigation led to the discovery of potent inhibitors with improved DMPK properties.

Published
2008
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