Preclinical Characterization of SCH 900518

Preclinical Characterization of SCH 900518,A Novel Mechanism-Based Inhibitor of HCV NS3 Protease

44th EASL Aril 23-26 2009 Copenhagen Denmark
Reported by Jules Levin

X. Tong, A. Arasappan, F. Bennett, R. Chase, B. Feld, Z. Guo, A. Hart, V. Madison, B. Malcolm, J. Pichardo, A. Prongay, R. Ralston, A. Skelton, E. Xia, F. G. Njoroge Schering-Plough Research Institute, Kenilworth, New Jersey, USA

Abstract
Background: Small molecule hepatitis C virus (HCV) nonstructural protein 3 (NS3) protease inhibitors have shown antiviral activity as monotherapy and in combination with pegylated interferon-alfa and ribavirin in clinical trials; however, clinical efficacy can be limited by inadequate drug exposure and development of viral resistance. Improvement in inhibitor potency and pharmacokinetic properties offers opportunities to overcome such limitations and to further increase SVR.

Methods: Inhibition of HCV NS3 protease was measured using a single-chain NS3 (3-181)/4A protease. The antiviral effect and resistance study of protease inhibitors were evaluated using genotype 1b HCV replicon cells.

Results: Combination of medicinal chemistry and structure-based design has led to the discovery of SCH 900518, a novel ketoamide protease inhibitor which forms a reversible covalent bond with the active site serine with an inhibition constant (Ki*) of 7 nM.

SCH 900518 showed a 10-fold improvement in replicon potency (EC90 = 40 nM) compared to boceprevir and telaprevir. In biochemical assays, SCH 900518 was active against proteases of genotypes 1a, 1b, 2, and 3.

A 2-week treatment with 5 x EC90 of the inhibitor reduced replicon RNA by 3-log.

High exposures of SCH 900518 had minimal effects on a variety of human normal and tumor cell lines.

Selection of replicon cells with SCH 900518 resulted in outgrowth of several major resistant mutants (T54A/S, A156S/T/V). Preclinical cross-resistance studies demonstrated that the majority of mutations against boceprevir and telaprevir showed similar fold loss of activity against all three inhibitors; however,

SCH 900518 retained more activity against these mutants due to its higher intrinsic potency. Combination treatment with interferon-alfa enhanced inhibition of replicon RNA and suppressed emergence of resistant replicon colonies, supporting the use of SCH 900518/peginterferon combination therapy in the clinic.

Conclusions: The preclinical characterization of SCH 900518 supports its progression toward clinical evaluation of safety, pharmacokinetic, and pharmacodynamic parameters.

References
1. Manns MP et al. Lancet. 2001;358:958-965.
2. Fried MW et al. N Engl J Med. 2002;347:975-982.
3. Schiff E et al. 43rd Annual Meeting of the European Association for the Study of the Liver; April 23-27, 2008; Milan, Italy.
4. Malcolm BA et al. Antimicrob Agents Chemother. 2006;50:1013-1020.
5. Taremi SS et al. Protein Sci. 1998;7:2143-2149.
6. Zhang R et al. Anal Biochem. 1999;270:268-275.
7. Tong X et al. Antiviral Res. 2008;77:177-185.