Design, synthesis, and structure-activity relationship of a bicyclic HBV capsid assembly modulator chemotype leading to the identification of clinical candidate AB-506

Bioorg Med Chem Lett. 2023 Oct 1:94:129456. doi: 10.1016/j.bmcl.2023.129456. Epub 2023 Aug 25.

Abstract

Disruption of the HBV capsid assembly process through small-molecule interaction with HBV core protein is a validated target for the suppression of hepatitis B viral replication and the development of new antivirals. Through combination of key structural features associated with two distinct series of capsid assembly modulators, a novel aminochroman-based chemotype was identified. Optimization of anti-HBV potency through generation of SAR in addition to further core modifications provided a series of related functionalized aminoindanes. Key compounds demonstrated excellent cellular potency in addition to favorable ADME and pharmacokinetic profiles and were shown to be highly efficacious in a mouse model of HBV replication. Aminoindane derivative AB-506 was subsequently advanced into clinical development.

Keywords: Aminoindane; Capsid assembly modulator; HBV core protein; Hepatitis B virus.

MeSH terms

  • Animals
  • Antiviral Agents* / pharmacology
  • Capsid Proteins*
  • Capsid*
  • Carbamates* / chemistry
  • Carbamates* / pharmacology
  • Disease Models, Animal
  • Hepatitis B virus / drug effects
  • Hepatitis B virus / metabolism
  • Indenes* / chemistry
  • Indenes* / pharmacology
  • Mice
  • Structure-Activity Relationship
  • Triazoles* / chemistry
  • Triazoles* / pharmacology

Substances

  • Antiviral Agents
  • Capsid Proteins
  • AB-506
  • Carbamates
  • Indenes
  • Triazoles