Liver Targeting Dihydroquinolizinone (DHQ) Molecules as Hepatitis B Virus Antivirals with Reduced Toxicity - ABSTRACT
Hepatitis B virus chronically infects 258 million people worldwide and causes 880 thousand deaths annually due
to cirrhosis, hepatocellular carcinoma (HCC) and liver failure. The current standard of care medications, including
pegylated interferon alpha that regulates host antiviral immune response and nucleos(t)ide analogues that inhibit
viral DNA polymerase, can potently suppress viral replication, but fail to induce the loss of HBV surface antigen
(HBsAg), an indication of successful immune control or the functional cure of chronic hepatitis B, in the vast
majority of the treated patients. Therefore, the development of novel antivirals with a new mechanism that can
activate the host antiviral immune response is required to achieve the functional cure of chronic hepatitis B
(CHB). A dihydroquinolizinone (DHQ) RG-7834, a small molecule discovered by Roche, can rapidly reduce
hepatitis B virus (HBV) RNA levels, and hence almost all viral gene products, including HBsAg. This represents
an entirely new chemotype of HBV antivirals and a new approach for CHB control. However, the observation of
neurotoxicity in RG-7834 prohibits its systemic use for the management of CHB. We hypothesize that this side
effect can be minimized or eliminated by producing liver selective and CNS refractory DHQ antivirals. In support
of this hypothesis, we have recently designed and synthesized a novel series of bis-carboxylic acid based DHQ
derivatives that are shown, for the first time in this series, to have organic anion transporting polypeptide (OATP)
substrate properties, which facilitates selective distribution of the compounds to the therapeutic site of action
(liver), relative to the blood stream. This effort led to the discovery of an early lead, called DHQ-65042, which is
potent in both biochemical and cellular assays (EC50 = 23 nM in HepG2.2.15 cell line), while demonstrating
considerable safety improvement potential in comparison to RG-7834, such as low blood-brain barrier (BBB)
penetration (in vitro assay) and high in vivo liver selectivity over plasma (liver/plasma ratio is 37.8 in a mouse PK
study). This novel series of liver targeting DHQs are promising for improving safety profiles through limited
distribution to the blood stream, the brain, and other body tissues, though the exposure of DHQ-65042 in the
liver from the oral route of a pharmacokinetic (PK) study is moderate. In this R21 proposal, to validate the
feasibility of developing novel liver targeting DHQ derivatives as hepatitis B virus surface antigen reducers with
practical value, we will perform lead optimization to improve the liver exposure to an efficacious level with low
exposure in plasma maintained, and identify a balance window between hepatoselectivity and GI/ liver
absorption of new leads through the works proposed in three aims. Successful completion of this project will
allow us to develop a new generation of DHQs that are selectively delivered to livers with concentrations sufficient
enough to significantly reduce HBsAg and have better safety profiles, and to provide a new lead ready for in vivo
toxicity and efficacy studies.
