EASL/PPI-461, A POTENT AND SELECTIVE HCV NS5A INHIBITOR WITH ACTIVITY AGAINST ALL HCV GENOTYPES

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EASL/PPI-461, A POTENT AND SELECTIVE HCV NS5A INHIBITOR WITH ACTIVITY AGAINST ALL HCV GENOTYPES

IDENTIFICATION AND CHARACTERIZATION OF PPI-461, A POTENT AND SELECTIVE HCV NS5A INHIBITOR WITH ACTIVITY AGAINST ALL HCV GENOTYPESR. Colonno, E. Peng, M. Bencsik, N. Huang, M. Zhong, A. Huq, Q. Huang, J. , L. Li Presidio Pharmaceuticals, San Francisco, CA, USA. *rich@...Background: Several mechanistic classes of oral HCV inhibitors are currently undergoing clinical development. Inhibitors of NS5A have distinguished themselves by their picomolar potency and broad genotype spectrum in HCV replicon assays. Here we report the discovery and preclinical profile of PPI-461, a newly discovered NS5A inhibitor being advanced toward clinical studies.Methods: Antiviral potency, combination and resistance studies utilized standard HCV replicon systems (genotype

1a and 1b). HCV spectrum studies employed stable or transient replicon assays with insertion of NS5A gene segments from other HCV genotypes (2a, 3a, 4a, 5a, 6a and 7a) into an HCV 1b backbone. Pharmacokinetic studies utilized IV and PO administration of PPI-461 in rats, monkeys and dogs. Extensive ADME and toxicology profiling has been performed in vitro and in rats and monkeys.Results: PPI-461 was identified through an extensive medicinal chemistry effort and exhibits EC50s of 0.2 and 0.01 nM in HCV 1a and 1b replicon assays, respectively. Antiviral activity (EC50s of 0.1-19 nM) is maintained against all other HCV genotypes in transient/stable replicon assays. Cellular cytotoxicity levels (CC50) are >10 uM in several cell lines and no activity is observed against several other viruses (including BVDV) at 10 uM. PPI-461 is additive to synergistic (CIs 0.29-0.89) when combined with IFN, NS3

protease, NS5B nucleoside and non-nucleoside inhibitors. Resistance studies showed that variants with high levels of resistance could be generated, especially with genotype 1a, but required multiple amino acid substitutions within the NS5A gene. PPI-461 shows excellent stability in liver microsomes and no significant inhibition against P450 isozymes at 10 uM. PPI-461 exhibits good oral bioavailability in rats, monkeys and dogs, with enhanced liver concentrations and plasma half-lives suggestive of once daily dosing in humans. Toxicology studies in rats and monkeys showed that PPI-461 is well tolerated at plasma exposure levels >100,000-fold HCV 1a EC50 levels.Conclusion: HCV NS5A protein plays a critical role in the HCV viral replicative cycle and is an attractive target for antiviral intervention. PPI-461 is a newly discovered selective and broadly potent inhibitor of HCV NS5A protein with

a favorable preclinical profile supportive of advancement into clinical trial.

http://Hepatitis Cnewdrugs.blogspot.com/2010/04/easlppi-461-potent-and-selective-hcv.html