Identification of BMS-200475 as a Novel and Potent Inhibitor of Hepatitis B Virus Replication

BMS-200475 was first reported as having rather limited antiviral activity against herpesviruses. At ICAAC (September 1996), its very potent activity against human hepatitis B virus (HBV) was announced. At this meeting (ICAR), there were, in addition, 3 poster presentations.

BMS-200475, a Novel Carbocyclic 2-Deoxyguanosine Analog with Potent and Selective Anti-Hepatitis B Virus Activity in Vitro
G.S. Bisacchi, et al

BMS-200475, a New Anti-Hepatitis B Compound; Metabolic Studies and Comparison with 3TC, Penciclovir, and Lobucavir
G. Yamanaka, et al

BMS-200475 is a chiral compound, that means that its mirror image (enantiomer) is a different compound (as a left hand differs from a right hand). Interestingly the enantiomer has poor activity against HBV. The chemical synthesis gives BMS-200475 with good enantiomeric purity (>99%) in 20 g batches.

The phosphorylation of BMS-200475 to its active triphosphate form is the same in uninfected and HBV transfected cells. Therefore there is no selectivity due to preferential phosphorylation in HBV infected cells. However, BMS-200475 triphosphate is a powerful inhibitor of HBV DNA polymerase (K_i = 0.0012 uM) compared with human cellular polymerases (K_i less than or equal to18 uM). It is this difference that accounts for the high potency of BMS-200475 against HBV (EC50 = 0.004 uM) compared with inhibition of cell replication (CC₅₀ = 30 uM).

In the woodchuck model, BMS-200475 at 0.1 mg/kg once daily quickly reduced woodchuck hepatitis B virus DNA to undetectable levels in all seven animals. Furthermore, the viral DNA levels remained undetectable for four to eight weeks after therapy before returning to base line.

A phase I trial in healthy subjects indicates good bioavailablity of BMS-200475 after oral absorption. A single daily dose of 5 mg should give plasma concentrations of drug above the EC50 value against HBV for 24 hours