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Preclinical Characterization of ABT-072: A Novel Non-Nucleoside HCV Polymerase Inhibitor
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Reported by Jules Levin
44th Annual Meeting of the European Association for the Study of the Liver ( EASL), Copenhagen, Denmark, 22-26 April 2009
R. Wagner*, C. Maring, P. L. Donner, J. T. Randolph, A. C. Krueger, T. W. Rockway, J. K. Pratt, D. Liu, M. Tufano, W. M. Kati,
Y. Liu, H. B. Lim, G. Koev, J. M. Beyer, R. Mondal, T. J. Reisch, P. Krishnan, D. W. A. Beno, Y. Y. Lau, J. Shen, J. S. Fischer,
Y. Gao, A. Molla
Abbott Laboratories, Abbott Park, IL, USA
AUTHOR SUMMARY
ABT-072 is:
· a potent non-nucleoside genotype-1-selective HCV polymerase inhibitor with 5-9 fold greater potency than ABT-333 in the presence of 40% plasma.
· highly permeable in the Caco-2 permeability assay and shows excellent PK in rat and dog, with preferential distribution into liver tissue in all species tested.
· a weak-to-moderate inhibitor of CYPs, that is metabolized by multiple isoforms of the enzyme, indicating low potential for eliciting clinically significant drug-drug interactions.
BACKGROUND
HCV is an enveloped positive-strand RNA virus that replicates primarily in the cytoplasm of hepatocytes. The RNA polymerase (NS5B) encoded by the HCV genome has been shown to be indispensable for HCV replication making this key viral enzyme an attractive drug target. HCV polymerase contains the
canonical structural features found in most polynucleotide polymerases, yet HCV polymerase has a unique structural architecture and two noteworthy enzymatic properties that distinguish it from mammalian polymerases: 1) it synthesizes RNA using a RNA template, whereas virtually all mammalian polymerases use DNA as the template source, and 2) unlike mammalian polymerases, HCV polymerase has the ability to initiate RNA synthesis without using a RNA oligonucleotide primer.
Mechanistically, nucleoside and non-nucleoside HCV polymerase inhibitors are differentiated by virtue of differing binding sites. Consequently, nucleoside inhibitors act as substrates and inhibit elongation by chain termination whereas non-nucleoside inhibitors more typically inhibit the initiation phase of RNA synthesis. Non-nucleoside inhibitors that bind to each of the known inhibitor binding sites have advanced to human clinical studies and exhibit in vivo activity in HCV infected patients.
ABT-072 is a novel non-nucleoside HCV polymerase inhibitor with potent activity against genotype 1a and 1b HCV replicons. This compound is currently being evaluated for safety, pharmacokinetics and antiviral efficacy in chronically-infected HCV genotype 1-infected patients. The objective of this report will be to disclose the potency, pharmacokinetic and ADME profile of ABT-072 in preclinical model systems.
METHODS
The polymerase inhibition profile and selectivity of ABT-072 were determined with a panel of HCV NS5B and human polymerase enzymes. Strains were cloned from plasmid DNA or from existing replicon cells and amplified, transfected, expressed and purified using methods described previously. Inhibition of human DNA polymerases by ABT-072 was determined by Replizyme Ltd. In cell culture, HCV replicon potency was assessed in the presence and absence of 40% human plasma; patient samples employed the use of a shuttle vector system. ADME studies with 3H-ABT-072 were conducted in vitro with human microsomes and hepatocytes and in vivo in rats. ABT-072 plasma pharmacokinetics in rat, dog and monkey were determined after IV and oral dosing, and liver drug levels at 12h after oral dosing.
ABT-072 did not inhibit a panel of human polymerases (IC50s = >100,000 nM)
· Human polymerase ß
· Human polymerase γ (polymerase)
· Human polymerase γ (reverse transcriptase)
· Human DNA dependent RNA polymerase II
· Human DNA dependent RNA polymerase III
· ABT-072 is a weak-to-moderate inhibitor of CYP2C19, 2C9 and 2D6.
· No significant inhibition evidenced for CYP1A2 or 3A4/5.
· ABT-072 metabolized by multiple isoforms of cytochrome P450 enzymes (data not shown).
· ABT-072 has low potential to elicit clinically significant drug-drug interactions.
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