Hepatitis B is a major global health problem affecting almost 270 million people worldwide and accounting for deaths exceeding 800,000 per year, resulting primarily from progression to liver fibrosis, cirrhosis and liver cancer. There is a great deal of interest in identifying agents that inhibit viral replication in a manner that is distinct from existing nucleos(t)ide-based viral polymerase inhibitors. The encapsidation of pregenomic RNA (pgRNA) by dimeric units of hepatitis B virus core protein (Cp) is an essential step in the HBV viral life cycle, facilitating viral genome relaxed circular DNA (rcDNA) synthesis, infectious virion production and maintenance of a nuclear covalently closed circular DNA (cccDNA) pool. Small molecules that bind at the dimer:dimer interface of Cp have been shown to prevent the encapsidation of pgRNA and there is clinical validation for the use of such agents in the inhibition of HBV replication. Through combination of key structural features associated with different HBV capsid inhibitors, a novel series of functionalized aminochromanes was identified. SAR optimization of cellular anti-HBV activity led to the identification of a series of related aminoindane derivatives. Lead optimization produced potent compounds that dose dependently reduced HBV DNA levels by up to 3.0 log10 in an in vivo hydrodynamic injection (HDI) mouse model of HBV infection. X-ray crystallographic analysis of key analogs bound to the assembly deficient Y132A mutant of the assembly domain of Cp identified the key electrostatic and hydrophobic interactions of compounds within the Cp binding pocket. Furthermore, mechanism of action studies indicated that the aminoindanes induced the formation of HBV capsid particles devoid of pgRNA. Based on excellent in vitro and in vivo antiviral activity and desirable in vitro ADME properties in addition to a pharmacokinetic profile consistent with once daily dosing, aminoindane derivative AB-506 was selected for progression into clinical development. In phase 1b trials, q.d. dosing of AB-506 in HBV patients resulted in multi-log10 reductions in HBV DNA and RNA, however, further development was discontinued due to the observation of ALT elevation in some subjects.

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

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ACS Fall 2022

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