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5 results on '"Blazel JK"'

1. Discovery of tricyclic 5,6-dihydro-1H-pyridin-2-ones as novel, potent, and orally bioavailable inhibitors of HCV NS5B polymerase.

Author

Ruebsam F, Murphy DE, Tran CV, Li LS, Zhao J, Dragovich PS, McGuire HM, Xiang AX, Sun Z, Ayida BK, Blazel JK, Kim SH, Zhou Y, Han Q, Kissinger CR, Webber SE, Showalter RE, Shah AM, Tsan M, Patel RA, Thompson PA, Lebrun LA, Hou HJ, Kamran R, Sergeeva MV, Bartkowski DM, Nolan TG, Norris DA, Khandurina J, Brooks J, Okamoto E, and Kirkovsky L

Subjects
Antiviral Agents pharmacokinetics, Chemistry, Pharmaceutical, Crystallography, X-Ray, Drug Evaluation, Preclinical, Genotype, Hepacivirus drug effects, Hepatitis C, Molecular Structure, RNA-Dependent RNA Polymerase, Viral Nonstructural Proteins antagonists & inhibitors, Biological Availability, Drug Design, Structure-Activity Relationship
Abstract

A novel series of non-nucleoside small molecules containing a tricyclic dihydropyridinone structural motif was identified as potent HCV NS5B polymerase inhibitors. Driven by structure-based design and building on our previous efforts in related series of molecules, we undertook extensive SAR studies, in which we identified a number of metabolically stable and very potent compounds in genotype 1a and 1b replicon assays. This work culminated in the discovery of several inhibitors, which combined potent in vitro antiviral activity against both 1a and 1b genotypes, metabolic stability, good oral bioavailability, and high C(12) (PO)/EC(50) ratios.

Published
2009
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2. 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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3. 5,6-Dihydro-1H-pyridin-2-ones as potent inhibitors of HCV NS5B polymerase.

Author

Ruebsam F, Tran CV, Li LS, Kim SH, Xiang AX, Zhou Y, Blazel JK, Sun Z, Dragovich PS, Zhao J, McGuire HM, Murphy DE, Tran MT, Stankovic N, Ellis DA, Gobbi A, Showalter RE, Webber SE, Shah AM, Tsan M, Patel RA, Lebrun LA, Hou HJ, Kamran R, Sergeeva MV, Bartkowski DM, Nolan TG, Norris DA, and Kirkovsky L

Subjects
Administration, Oral, Animals, Biological Availability, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacokinetics, Haplorhini, Pyridones administration & dosage, Pyridones chemistry, Pyridones pharmacokinetics, Structure-Activity Relationship, DNA-Directed RNA Polymerases antagonists & inhibitors, Enzyme Inhibitors pharmacology, Pyridones pharmacology, Viral Nonstructural Proteins antagonists & inhibitors
Abstract

5,6-Dihydro-1H-pyridin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4ad displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; IC(50) (1a)<25nM, EC(50) (1b)=16nM), good in vitro DMPK properties, as well as moderate oral bioavailability in monkeys (F=24%).

Published
2009
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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 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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5. 4-(1,1-Dioxo-1,4-dihydro-1lambda6-benzo[1,4]thiazin-3-yl)-5-hydroxy-2H-pyridazin-3-ones as potent inhibitors of HCV NS5B polymerase.

Author

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

Subjects
Caco-2 Cells, Crystallography, X-Ray methods, Drug Design, Hepacivirus drug effects, Humans, Inhibitory Concentration 50, Models, Chemical, Molecular Conformation, Pyridazines chemistry, Structure-Activity Relationship, Thiazines chemistry, Thiazines pharmacology, Time Factors, Chemistry, Pharmaceutical methods, Hepacivirus enzymology, Microsomes, Liver enzymology, Pyridazines chemical synthesis, Pyridazines pharmacology, Thiazines chemical synthesis, Viral Nonstructural Proteins antagonists & inhibitors, Viral Nonstructural Proteins chemistry
Abstract

4-(1,1-Dioxo-1,4-dihydro-1lambda(6)-benzo[1,4]thiazin-3-yl)-5-hydroxy-2H-pyridazin-3-one analogs were discovered as a novel class of inhibitors of HCV NS5B polymerase. Structure-based design led to the identification of compound 3a that displayed potent inhibitory activities in biochemical and replicon assays (1b IC(50)<10 nM; 1b EC(50)=1.1 nM) as well as good stability toward human liver microsomes (HLM t(1/2)>60 min).

Published
2008
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