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Conformationally Constrained Isoquinolinones as Orally Efficacious Hepatitis B Capsid Assembly Modulators.
- Source :
-
ACS medicinal chemistry letters [ACS Med Chem Lett] 2024 Sep 03; Vol. 15 (9), pp. 1627-1634. Date of Electronic Publication: 2024 Sep 03 (Print Publication: 2024). - Publication Year :
- 2024
-
Abstract
- Isoquinolinone-based HBV capsid assembly modulators that bind at the dimer:dimer interface of HBV core protein have been shown to suppress viral replication in chronic hepatitis B patients. Analysis of their binding mode by protein X-ray crystallography has identified a region of the small molecule where the application of a constraint can lock the preferred binding conformation and has allowed for further optimization of this class of compounds. Key analogues demonstrated single digit nM EC <subscript>50</subscript> values in reducing HBV DNA in a HepDE19 cellular assay in addition to favorable ADME and pharmacokinetic properties, leading to a high degree of oral efficacy in a relevant in vivo hydrodynamic injection mouse model of HBV infection, with 12e effecting a 3 log <subscript>10</subscript> decline in serum HBV DNA levels at a once daily dose of 1 mg/kg. Additionally, maintenance of activity was observed in clinically relevant HBV core protein variants T33N and I105T.<br />Competing Interests: The authors declare no competing financial interest.<br /> (© 2024 American Chemical Society.)
Details
- Language :
- English
- ISSN :
- 1948-5875
- Volume :
- 15
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- ACS medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 39291037
- Full Text :
- https://doi.org/10.1021/acsmedchemlett.4c00388