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

Autor:	Jingjing Zhao, Frank Ruebsam, Rupal Patel, Douglas E. Murphy, Tran Chinh Viet, Stephen E. Webber, Charles R. Kissinger, Nebojsa Stankovic, Lian-Sheng Li, Darian M. Bartkowski, Richard E. Showalter, Qiang Zhao, Mei Tsan, Benjamin K. Ayida, Zhongxiang Sun, Ruhi Kamran, Leo Kirkovsky, Peter S. Dragovich, Jennifer Brooks, Amit M. Shah, Laurie A. LeBrun, Maria V. Sergeeva, Thomas M. Bertolini, Thomas G. Nolan, Daniel A. Norris, Yuefen Zhou
Rok vydání:	2008
Předmět:	Stereochemistry Clinical Biochemistry Pharmaceutical Science Administration Oral Hepacivirus Viral Nonstructural Proteins Biochemistry Chemical synthesis Antiviral Agents Structure-Activity Relationship In vivo Oral administration Drug Discovery Structure–activity relationship Animals Combinatorial Chemistry Techniques Humans Replicon Molecular Biology chemistry.chemical_classification biology Molecular Structure Chemistry Organic Chemistry Nucleotidyltransferase RNA-Dependent RNA Polymerase Rats Pyridazines Enzyme Enzyme inhibitor Drug Design biology.protein Microsomes Liver Molecular Medicine
Zdroj:	Bioorganicmedicinal chemistry letters. 18(11)
ISSN:	1464-3405
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1e51c8e956fdb226b2d076056f8c00c0 https://pubmed.ncbi.nlm.nih.gov/18457949 Zobrazit plný text záznamu Full Text from ScienceDirect