Discovery of fluorobenzimidazole HCV NS5A inhibitors

Highlights of the Structure–Activity Relationships of Benzimidazole Linked Pyrrolidines Leading to the Discovery of the Hepatitis C Virus NS5A Inhibitor Pibrentasvir (ABT-530)

“…While higher LogD values, lower aqueous Of particular note, in 2016 Randolph et al reported that 5fluoro substitution of the benzimidazole linker of analogs 18 and 29, provided compounds of nearly identical potencies in genotypes 1−4 and 6, while also increasing drug plasma levels after oral dosing in mice. 35 The hypothesis underlying the improvement of oral PK upon benzimidazole fluorination predicted that the halogenation would decrease the basicity of the benzimidazole nitrogens. 36 In order to verify that sufficient antiviral activity of this potentially promising modification extended to other analogs with respect to virology and PK, additional compounds were synthesized.…”

“…As the fluorobenzimidazole-linked compounds were previously shown to improve oral PK characteristics, 35 final synthetic efforts sought to examine the effects of varying the Moc-Val-"end-capping" groups, with the aim of further improving the virological profile, while conserving the central core structure of 34 and 35. Table 9 summarizes the antiviral activity of the best of these compounds against replicons of wild-type genotypes 1−6.…”

“…Of particular note, in 2016 Randolph et al reported that 5-fluoro substitution of the benzimidazole linker of analogs 18 and 29 , provided compounds of nearly identical potencies in genotypes 1–4 and 6, while also increasing drug plasma levels after oral dosing in mice . The hypothesis underlying the improvement of oral PK upon benzimidazole fluorination predicted that the halogenation would decrease the basicity of the benzimidazole nitrogens .…”

Electrochemically mediated fluoroalkylation/cyclization of unactivated alkenes: synthesis of polycyclic benzimidazoles containing a CF3 group

“…8 In addition, fluorinated benzimidazole derivatives possess improved pharmacokinetic properties. 9 Due to their broad biological value, the synthesis of functionalized fluorinated polycyclic imidazoles has been the focus of chemists' attention in recent years. Selective C–H alkylation of benzimidazoles with intramolecular alkenes would provide atomically economical methods to construct these compounds rapidly.…”