title: Inhibition of human hepatitis B virus (HBV) by a novel non-nucleosidic compound in a transgenic mouse model.
abstract: BAY 41-4109 is a member of a class of heteroaryl-pyrimidines that was recently identified as potent inhibitors of human hepatitis B virus (HBV) replication. We have investigated the antiviral activity of BAY 41-4109 (methyl (R)-4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridinyl)-6-methyl-1,4-dihydro-pyrimidine-5-carboxylate) in HBV-transgenic mice (Tg [HBV1.3 fsX(-)3'5']). Bay 41-4109 was administered per os using different schedules (b.i.d. or t.i.d. for up to 28 days) and dosages ranging from 3 to 30 mg/kg. The compound reduced viral DNA in the liver and in the plasma dose-dependently with efficacy comparable to 3TC. In contrast to 3TC-treated mice, we found a reduction of cytoplasmic hepatitis B virus core antigen (HBcAg) in liver sections of BAY 41-4109-treated mice, which indicated a different mode of action. Pharmacokinetic studies in mice have shown rapid absorption, a bioavailability of 30% and dose-proportional plasma concentrations. We conclude that BAY 41-4109 is a new anti-HBV drug candidate.
authors.affiliation: Department of Antiinfective Research, Bayer AG Pharmaceutical Research Centre, D-42096 Wuppertal, Germany. olaf.weber@bayer.com
authors.forename: O
authors.initials: O
authors.lastname: Weber
authors.forename: K-H
authors.initials: KH
authors.lastname: Schlemmer
authors.forename: E
authors.initials: E
authors.lastname: Hartmann
authors.forename: Ina
authors.initials: I
authors.lastname: Hagelschuer
authors.forename: A
authors.initials: A
authors.lastname: Paessens
authors.forename: E
authors.initials: E
authors.lastname: Graef
authors.forename: K
authors.initials: K
authors.lastname: Deres
authors.forename: S
authors.initials: S
authors.lastname: Goldmann
authors.forename: U
authors.initials: U
authors.lastname: Niewoehner
authors.forename: J
authors.initials: J
authors.lastname: Stoltefuss
authors.forename: D
authors.initials: D
authors.lastname: Haebich
authors.forename: H
authors.initials: H
authors.lastname: Ruebsamen-Waigmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Wohlfeil
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002478:Cells, Cultured; D004279:DNA, Viral / Q000737:chemistry / Q000235:genetics; D005260:Female; D006509:Hepatitis B / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D006512:Hepatitis B Core Antigens / Q000032:analysis; D006515:Hepatitis B virus / Q000235:genetics / Q000254:growth & development*; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000821:virology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009693:Nucleic Acid Hybridization; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000998:Antiviral Agents; C464059:BAY 41-4109; D004279:DNA, Viral; D006512:Hepatitis B Core Antigens; D011725:Pyridines; D011743:Pyrimidines