MK-8325: A silyl proline-containing NS5A inhibitor with pan-genotype activity for treatment of HCV

Discovery of MK-6169, a Potent Pan-Genotype Hepatitis C Virus NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Substitutions

“…However, cis-2,6diethyl THP analog 19 exhibited reduced potency against all the genotypes tested, especially on GT2b L31M with a ∼100fold loss in potency as compared with the corresponding cis-2,6-dimethyl THP analog 17, indicating that a larger substituent was not tolerated. 2,2-Dimethyl substituted THP analogs (20,21) as well as the 2-spiro-cyclopropyl THP analog (22) all displayed good potency against all the genotypes tested. Additionally, the 8-oxabicyclo[3.…”

“…Our efforts in the research on HCV NS5A inhibitors have progressed over time. − Multiple NS5A inhibitors, including MK-4882, MK-8325, and MK-8742, , have been identified. MK-8742 (elbasvir, Figure , Table ) is one of the two components in Zepatier which has gained FDA approval for the treatment of GT1 and GT4 chronic HCV infection.…”

“…It also showed improved C 24h relative to the other compounds. The rat PK exposure of the 2-spiro-cyclopropyl THP analog(22) was low and so were the rat PK exposures of 23 and 24. The dog PK profiles of 17, 18, and 21 were also examined.…”

Fluorine-Containing Prolines: Synthetic Strategies, Applications, and Opportunities

“…From the mechanistic standpoint, the redox-active complex 285 formed first, which In 2020, Grygorenko and co-workers from Enamine reported on a practical gram-scale synthesis of racemic cis-5-trifluoromethyl proline. 145 Reaction of pyrrole (288) with CF 3 I and Fenton's reagent (FeSO 4 /H 2 O 2 /H 2 SO 4 ) 146 gave the trifluoromethylated derivative 289 in 76% yield (Scheme 49). N-Boc protection, followed by treatment with butyl lithium and carbon dioxide, gave acid 290 in 57% yield.…”

“…Indeed, with the development of novel synthetic methods, a repertoire of fluorinated prolines dramatically increased during the past two decades. It is impossible to consider in this Perspective each individual example in details, but the list of recent bioactive structures with a fragment of fluorinated proline along with a brief description of their application are outlined in Figure . − …”