Aryl or heteroaryl substituted aminal derivatives of HCV NS5A inhibitor MK-8742

Discovery of Chromane Containing Hepatitis C Virus (HCV) NS5A Inhibitors with Improved Potency against Resistance-Associated Variants

“…During our previous SAR studies, efforts trying to differentiate the meta-and para-substitution on the phenyl group of compound 1 led to the conclusion that substitutions at both positions were tolerated. 26 For example, both compounds 2a and 2b (Figure 3) showed good potency against all genotypes tested (Table 1), indicating good tolerance of biaryl rings in this region. With these data in hand, we sought to explore the impact of 3,4-fused bicyclic groups, as "Z groups", with the goal of improving the potency against RAVs (Figure 3).…”

“…Previously, we determined that alkoxy substitutions on either the meta-or para-position of the phenyl group could improve the potency against GT2b and GT1a Y93H. 26 Thus, we incorporated oxygen atom(s) into the distal ring of the fused "Z groups" found in compounds 6 and 7. Incorporating one oxygen atom into the cyclopentyl ring of compound 6 yielded derivatives 8 and 9 (Table 3), with both compounds showing potency similar to compound 6.…”

“…Our strategy was to explore every region of the structure of compound 1 and identify SARs that could improve the potency against GT2b, GT1a Y93H, and GT1a L31V together and maintain the good potency against the other genotypes and mutants already achieved by compound 1 . Toward this end, we have reported SAR studies directed toward the “core”, − “Z” group, , “cap”, and proline modifications (Figure ). SAR studies around the “Z = aryl groups” yielded NS5A inhibitors with reduced potency shifts from GT1a to GT2b, GT1a Y93H, and GT1a L31V which had not been observed in our efforts around the alternative “core”, “Z = alkyl group”, “cap”, and proline modifications, clearly indicating the value of “Z = aromatic group” plays in the potency profiles of the tetracyclic indole-based NS5A inhibitors.…”

“…Toward this end, we have reported SAR studies directed toward the “core”, − “Z” group, , “cap”, and proline modifications (Figure ). SAR studies around the “Z = aryl groups” yielded NS5A inhibitors with reduced potency shifts from GT1a to GT2b, GT1a Y93H, and GT1a L31V which had not been observed in our efforts around the alternative “core”, “Z = alkyl group”, “cap”, and proline modifications, clearly indicating the value of “Z = aromatic group” plays in the potency profiles of the tetracyclic indole-based NS5A inhibitors. In a different study, we identified another important SAR that the C-1 fluoro substitution on the tetracyclic indole core could improve the potency against both GT2b and GT1a Y93H simultaneously .…”

Hepatitis C Virus Nonstructural 5A Protein (HCV-NS5A) Inhibits Hepatocyte Apoptosis through the NF-κb/miR-503/bcl-2 Pathway

“…The most recent study suggested that NS5A was a key factor in HCV treatment (Ikeda et al, 2016). Moreover, many NS5A inhibitors have been proven to effectively treat HCV (Gane et al, 2016), such as BMS-790052 (Gao et al, 2010), MK-8742 (Coburn et al, 2013; Yu et al, 2016), MK-8408 (Ling et al, 2016), ABT530 (Lin et al, 2015), GS-5816 (Mogalian et al, 2015), etc. Because drugs are expensive and have a resistance barrier, it is essential to identify the NS5A inhibition mechanism that can offer a new strategy for the future treatment of HCV.…”