Ombitasvir (ABT-267) is a hepatitis C virus (HCV) NS5A inhibitor with picomolar potency, pan-genotypic activity, and 50% effective concentrations (EC 50 s) of 0.82 to 19.3 pM against HCV genotypes 1 to 5 and 366 pM against genotype 6a. Ombitasvir retained these levels of potency against a panel of 69 genotype 1 to 6 chimeric replicons containing the NS5A gene derived from HCV-infected patients, despite the existence of natural sequence diversity within NS5A. In vitro resistance selection identified variants that conferred resistance to ombitasvir in the HCV NS5A gene at amino acid positions 28, 30, 31, 58, and 93 in genotypes 1 to 6. Ombitasvir was evaluated in vivo in a 3-day monotherapy study in 12 HCV genotype 1-infected patients at 5, 25, 50, or 200 mg dosed once daily. All patients in the study were HCV genotype 1a infected and were without preexisting resistant variants at baseline as determined by clonal sequencing. Decreases in HCV RNA up to 3.1 log 10 IU/ml were observed. Resistance-associated variants at position 28, 30, or 93 in NS5A were detected in patient samples 48 hours after the first dose. Clonal sequencing analysis indicated that wild-type virus was largely suppressed by ombitasvir during 3-day monotherapy, and at doses higher than 5 mg, resistant variant M28V was also suppressed. Ombitasvir was well tolerated at all doses, and there were no serious or severe adverse events. HCV genotype 1, predominant in North America, Europe, and Japan, accounts for 60% of the global infections (4-6). Genotype 2 infections are most prevalent in North America, Europe, and Japan, while genotype 3, 6, and 7 infections are predominant within various parts of Southeast Asia (3, 7-9). In Egypt, HCV infections are almost exclusively genotype 4, while genotype 5 is common in South Africa (10, 11). The levels of nucleotide sequence diversity between genotypes and between subtypes are 30 to 35% and 20 to 25%, respectively (12). The viral dynamics are rapid for HCV, with 10 12 virions being produced daily with a half-life of 45 min (13). Moreover, the RNA-dependent RNA polymerase of HCV is intrinsically error prone, and its lack of a proofreading function allows for introduction of approximately one nucleotide change per genome per replication cycle, which under drug pressure results in the expansion of preexisting drug resistant variants (13). These factors have created challenges in developing pan-genotypic HCV inhibitors with high genetic barriers to the development of resistance.HCV replication can be inhibited at various points in the replication cycle by targeting viral or host cell functions (14,15). For the treatment of HCV genotype 1, three HCV NS3/4A protease inhibitors (telaprevir, boceprevir, and simeprevir) and one nucleoside NS5B polymerase inhibitor (sofosbuvir), each in combination with pegylated interferon (pegIFN) and ribavirin (RBV), have received marketing approval in the United States and Europe. The sustained virologic response (SVR) rate increased from 40 to 52% with pegIFN and RBV regimens to 67...

We describe here N-phenylpyrrolidine-based inhibitors of HCV NS5A with excellent potency, metabolic stability, and pharmacokinetics. Compounds with 2S,5S stereochemistry at the pyrrolidine ring provided improved genotype 1 (GT1) potency compared to the 2R,5R analogues. Furthermore, the attachment of substituents at the 4-position of the central N-phenyl group resulted in compounds with improved potency. Substitution with tert-butyl, as in compound 38 (ABT-267), provided compounds with low-picomolar EC50 values and superior pharmacokinetics. It was discovered that compound 38 was a pan-genotypic HCV inhibitor, with an EC50 range of 1.7-19.3 pM against GT1a, -1b, -2a, -2b, -3a, -4a, and -5a and 366 pM against GT6a. Compound 38 decreased HCV RNA up to 3.10 log10 IU/mL during 3-day monotherapy in treatment-naive HCV GT1-infected subjects and is currently in phase 3 clinical trials in combination with an NS3 protease inhibitor with ritonavir (r) (ABT-450/r) and an NS5B non-nucleoside polymerase inhibitor (ABT-333), with and without ribavirin.

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