Hepatoselective Dihydroquinolizinone Bis-acids for HBsAg mRNA Degradation

Abstract

Chronic hepatitis B (CHB) is characterized by high levels of hepatitis B virus (HBV) surface antigen (HBsAg) in blood circulation. A major goal of CHB interventions is reducing or eliminating this antigenemia; however, there are currently no approved methods that can do this. A novel family of compounds with a dihydroquinolizinone (DHQ) scaffold has been shown to reduce circulating levels of HBsAg in animals, representing a first for a small molecule. Reductions of HBsAg were a result of the compound's effect on HBsAg mRNA levels. However, commercial development by Roche of a DHQ lead compound, RG-7834, was stopped due to undisclosed toxicity issues. Herein we report our effort to convert the systemic RG7834 compound to a hepatoselective DHQ analog to limit its distribution to the bloodstream and thus to other body tissues.

Figure 1

Structures of RG7834, two known hepatoselective molecules, and our proposed DHQ derivative 4 with an additional acid group through position 9.

Scheme 1. Synthesis of Bis-acids 14–21

Figure 2

(A) Activities of new DHQ derivatives to reduce HBsAg (EC₅₀). (B) Northern blot analysis of bis-acid 19 for HBV mRNA reduction (at 1 μM after 5 days of treatment). (C) Dose-dependent inhibition of 19 against PAPD 5 and 7 compared to RG7834.

Figure 3

(A) Substrate determination of 19 on OATP1B1 and OATP1B3. Estradiol 17-β glucuronide was used as a positive control. (B) BBB penetration potential in MDCK-MDR1 cells.

Figure 4

(A) ADME evaluation of 19. (B) PK profile of 19 through IV and PO routes. (C) Liver versus plasma distribution of 19 in the PO route. (D) Concentration of 19 in the liver over a 8 h time course.