title: Safety and antiviral activity of JTK-652: a novel HCV infection inhibitor.
abstract: BACKGROUND
  Standard treatment of chronic hepatitis C with pegylated interferon and ribavirin is associated with suboptimal virological response rates and substantial side effects. This study describes the in vitro and in vivo development of JTK-652, a novel pyrrolopyridazin-derived HCV infection inhibitor.
  
  
  METHODS
  JTK-652 was evaluated in multiple cell lines using an in vitro HCV infection model consisting of HCV pseudotype vesicular stomatitis virus bearing HCV E1/E2 envelope proteins. Safety, tolerability, pharmacokinetics and efficacy of JTK-652 were tested in a randomized double-blind and placebo-controlled study in healthy male volunteers (n=36) and chronic hepatitis C patients. A total of 10 HCV genotype-1-infected patients (treatment-naive [n=2] and treatment-experienced [n=8]) with HCV RNA>1x10(5) IU/ml received an oral dose of 100 mg JTK-652 three times daily or placebo (8:2 ratio) for 4 weeks.
  
  
  RESULTS
  JTK-652 showed potent inhibitory activity against HCV genotype 1a and 1b pseudotype viruses bearing HCV E1/E2 envelope proteins in HepG2 cells and in human primary hepatocytes. No significant clinical laboratory, vital sign, ECG or physical examination abnormalities were observed during the Phase I trial. JTK-652 was found to be well tolerated. No significant changes in HCV RNA levels compared with baseline were observed at the end of treatment.
  
  
  CONCLUSIONS
  Although results from the preclinical studies indicated that JTK-652 has well-established antiviral properties and a Phase I clinical trial has showed that JTK-652 was safe and well tolerated at a 100 mg three times daily dose level, plasma HCV RNA levels in chronically HCV-infected patients did not decrease during 28 days of dosing at a 100 mg three times daily dose level.
authors: Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, the Netherlands. j.debruijne@amc.nl
authors: Joep
authors: J
authors: de Bruijne
authors: Jilling F
authors: JF
authors: Bergmann
authors: Christine J
authors: CJ
authors: Weegink
authors: Carin M J
authors: CM
authors: van Nieuwkerk
authors: Robert J
authors: RJ
authors: de Knegt
authors: Yasumasa
authors: Y
authors: Komoda
authors: Jeroen J
authors: JJ
authors: van de Wetering de Rooij
authors: Andre
authors: A
authors: van Vliet
authors: Peter L M
authors: PL
authors: Jansen
authors: Richard
authors: R
authors: Molenkamp
authors: Janke
authors: J
authors: Schinkel
authors: Hendrik
authors: H
authors: Reesink
authors: Harry L A
authors: HL
authors: Janssen
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004311:Double-Blind Method; D005260:Female; D016174:Hepacivirus / Q000187:drug effects* / Q000472:pathogenicity; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011724:Pyridazines / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D011724:Pyridazines; D012367:RNA, Viral