title: Design, synthesis, and biological evaluation of triazolo-pyrimidine derivatives as novel inhibitors of hepatitis B virus surface antigen (HBsAg) secretion.
abstract: The high levels of hepatitis B virus (HBV) surface antigen (HBsAg)-bearing subviral particles in the serum of chronically infected individuals play an important role in suppressing HBV-specific immune response and are only mildly affected by the current small molecule therapies. Thus, a therapy that specifically reduces HBsAg serum levels could be used in combination therapy with nucleos(t)ide drugs or permit therapeutic vaccination for the treatment of HBV infection. Herein, we report the design, synthesis, and evaluation of novel triazolo-pyrimidine inhibitors (1, 3, and 4) of HBsAg cellular secretion, with activity against drug-resistant HBV variants. Extensive SAR led to substantial improvements in the EC(50) of the parent compound, 5 (HBF-0259), with the best being 3c, with EC(50) = 1.4 ± 0.4 μM, SI ≥ 36. The lead candidates, both 1a (PBHBV-001) and 3c (PBHBV-2-15), were well-tolerated in both normal and HBV-transgenic mice and exhibited acceptable pharmacokinetics and bioavailability in Sprague-Dawley rats.
authors.affiliation: School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, PR China.
authors.forename: Wenquan
authors.initials: W
authors.lastname: Yu
authors.forename: Cally
authors.initials: C
authors.lastname: Goddard
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Clearfield
authors.forename: Courtney
authors.initials: C
authors.lastname: Mills
authors.forename: Tong
authors.initials: T
authors.lastname: Xiao
authors.forename: Haitao
authors.initials: H
authors.lastname: Guo
authors.forename: John D
authors.initials: JD
authors.lastname: Morrey
authors.forename: Neil E
authors.initials: NE
authors.lastname: Motter
authors.forename: Kang
authors.initials: K
authors.lastname: Zhao
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Block
authors.forename: Andrea
authors.initials: A
authors.lastname: Cuconati
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Xu
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000188:drug therapy* / Q000821:virology; D006514:Hepatitis B Surface Antigens / Q000378:metabolism*; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D009154:Mutation; D063065:Organophosphonates / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D000068698:Tenofovir; D013777:Tetrazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; C528232:HBF 0259; D006514:Hepatitis B Surface Antigens; D063065:Organophosphonates; D011743:Pyrimidines; D013777:Tetrazoles; D019259:Lamivudine; C413685:entecavir; D006147:Guanine; D000068698:Tenofovir; D000225:Adenine