A high level of hepatitis B virus (HBV) surface antigen (HBsAg) in the serum of patients is a common feature of chronic hepatitis B (CHB), which infects 296 million people worldwide and causes 820 thousand deaths annually due to liver cirrhosis, hepatocellular carcinoma (HCC) and liver failure based on a WHO fact sheet from 2021. Reduction of HBsAg in the blood has become one of the three goals for a primary end point of CHB therapy, along with the reduction of viremia and normalization of liver derived transaminase levels in blood.<br/>Polyadenylating Polymerases 5 and 7 (PAPD 5 & 7) have become attractive targets for the therapy of chronic HBV infection. Since the first report of dihydroquinolizinone (DHQ) compound RG-7834 as an effective HBsAg reducer in 2018, dozens of structurally diversified DHQs have been disclosed in both scientific journals and patent publications. However, the CNS liability observed for RG-7834 raised a safety concern for this compound. Here, we report our effort to develop liver targeting DHQ derivatives. Through the installation of a recognition element for organic anion transporting polypeptide protein 1B1 (OATP1B1) and 1B3 (OATP1B3), we successfully developed DHQ derivatives as substrates of OATP1B1 and OATP1B3, resulting in a lead compound that is potent in biochemical and cellular assays, has low risk for penetrating blood-brain-barrier (BBB), and demonstrates high hepatoselectivity in liver versus plasma in a mouse pharmacokinetic (PK) study.

Liver targeting dihydroquinolizinones as HBsAg mRNA degraders

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ACS Fall 2022

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