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Antimicrobial Agents and Chemotherapy, April 2009, p. 1377-1385, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01058-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

In Vitro Activity and Preclinical Profile of TMC435350, a Potent Hepatitis C Virus Protease Inhibitor{triangledown} ,{dagger}

Tse-I Lin,1,2* Oliver Lenz,1,2 Gregory Fanning,1,2 Thierry Verbinnen,1,2 Frédéric Delouvroy,1,2 Annick Scholliers,1,2 Katrien Vermeiren,1,2 Åsa Rosenquist,3 Michael Edlund,3 Bertil Samuelsson,3 Lotta Vrang,3 Herman de Kock,1,2 Piet Wigerinck,1,2 Pierre Raboisson,1,2 and Kenneth Simmen1,2

Tibotec BVBA, Gen. De Wittelaan L11 B3, B-2800 Mechelen, Belgium,1 Tibotec Pharmaceuticals, Ltd., Eastgate Village, EastGate, Little Island, County Cork, Ireland,2 Medivir AB, P.O. Box 1086, SE-141 22 Huddinge, Sweden3

Received 6 August 2008/ Returned for modification 10 September 2008/ Accepted 16 January 2009

The hepatitis C virus (HCV) NS3/4A serine protease has been explored as a target for the inhibition of viral replication in preclinical models and in HCV-infected patients. TMC435350 is a highly specific and potent inhibitor of NS3/4A protease selected from a series of novel macrocyclic inhibitors. In biochemical assays using NS3/4A proteases of genotypes 1a and 1b, inhibition constants of 0.5 and 0.4 nM, respectively, were determined. TMC435350 inhibited HCV replication in a cellular assay (subgenomic 1b replicon) with a half-maximal effective concentration (EC50) of 8 nM and a selectivity index of 5,875. The compound was synergistic with alpha interferon and an NS5B inhibitor in the replicon model and additive with ribavirin. In rats, TMC435350 was extensively distributed to the liver and intestinal tract (tissue/plasma area under the concentration-time curve ratios of >35), and the absolute bioavailability was 44% after a single oral administration. Compound concentrations detected in both plasma and liver at 8 h postdosing were above the EC99 value measured in the replicon. In conclusion, given the selective and potent in vitro anti-HCV activity, the potential for combination with other anti-HCV agents, and the favorable pharmacokinetic profile, TMC435350 has been selected for clinical development.

* Corresponding author. Mailing address: Tibotec BVBA, Gen. De Wittelaan L11 B3, B-2800 Mechelen, Belgium. Phone: 32/15.46.1436. Fax: 32/15.28.6347. E-mail: tilin{at}its.jnj.com

{triangledown} Published ahead of print on 26 January 2009.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, April 2009, p. 1377-1385, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01058-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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