Discovery of ABT-267, a Pan-Genotypic Inhibitor of HCV NS5A

We describe here <i>N</i>-phenylpyrrolidine-based inhibitors of HCV NS5A with excellent potency, metabolic stability, and pharmacokinetics. Compounds with 2<i>S</i>,5<i>S</i> stereochemistry at the pyrrolidine ring provided improved genotype 1 (GT1) potency compared to the 2<i>R</i>,5<i>R</i> analogues. Furthermore, the attachment of substituents at the 4-position of the central <i>N</i>-phenyl group resulted in compounds with improved potency. Substitution with <i>tert</i>-butyl, as in compound <b>38</b> (ABT-267), provided compounds with low-picomolar EC₅₀ values and superior pharmacokinetics. It was discovered that compound <b>38</b> 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 <b>38</b> 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