Hexahydro-pyrrolo- and hexahydro-1H-pyrido[1,2-b]pyridazin-2-ones as potent inhibitors of HCV NS5B polymerase

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 18, 2008, Pages 5002-5005

  Ruebsam, Frank ^a   Sun, Zhongxiang ^a   Ayida, Benjamin K ^a   Webber, Stephen E ^a   Zhou, Yuefen ^a   Zhao, Qiang ^a   Kissinger, Charles R ^a   Showalter, Richard E ^a   Shah, Amit M ^a   Tsan, Mei ^a   Patel, Rupal ^a   LeBrun, Laurie A ^a   Kamran, Ruhi ^a   Sergeeva, Maria V ^a   Bartkowski, Darian M ^a   Nolan, Thomas G ^a   Norris, Daniel A ^a   Kirkovsky, Leo ^a  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

Hepatitis C Virus (HCV); Hexahydro 1H pyrido 1,2 b pyridazin 2 one; Hexahydro pyrrolo 1,2 b pyridazin 2 one; non nucleoside NS5B inhibitor; NS5B polymerase; Small molecule; Structure based design

Indexed keywords

ENZYME INHIBITOR; HEXAHYDRO 1H PYRIDO[1,2 B]PYRIDAZIN 2 ONE DERIVATIVE; HEXAHYDRO PYRROLO 1H PYRIDO[1,2 B]PYRIDAZIN 2 ONE DERIVATIVE; NONSTRUCTURAL PROTEIN 5B; PYRIDAZINE DERIVATIVE; UNCLASSIFIED DRUG; VIRUS ENZYME;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; CYTOTOXICITY; DRUG ACTIVITY; DRUG HALF LIFE; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; GENOTYPE; HEPATITIS C VIRUS; HUMAN; HUMAN CELL; LIVER MICROSOME; NONHUMAN; STRUCTURE ACTIVITY RELATION;

ANTIVIRAL AGENTS; COMBINATORIAL CHEMISTRY TECHNIQUES; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; HEPACIVIRUS; HUMANS; MICROSOMES, LIVER; MOLECULAR STRUCTURE; PYRIDAZINES; STRUCTURE-ACTIVITY RELATIONSHIP; VIRAL NONSTRUCTURAL PROTEINS;

HEPATITIS C VIRUS;

EID: 51349119976     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.08.017     Document Type: Article

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29. 2 at pH 7.6 and an inhibitor concentration of 2-10 mM. Diffraction data were collected to a resolution of 2.3 Å for compound 4c. The crystal structure discussed in this paper has been deposited in the Protein Databank (www.rcsb.org) with entry code: 3CVK. Full structure determination details are provided in the PDB entry.
30. Cynomolgus monkeys; dose: 1 mg/kg; Formulation (for both PO and IV administration): 1% DMSO, 9.9% Cremophor EL in 50 mM PBS, pH 7.4.
31. po/(1-CL/Q) where Q = 44 mL/min/kg (hepatic blood flow in cynomolgus monkey) and CL = 3.3 mL/min/kg (clearance in cynomolgus monkey after IV administration)