1 research outputs found
Design and Synthesis of P2–P4 Macrocycles Containing a Unique Spirocyclic Proline: A New Class of HCV NS3/4A Inhibitors
A new class of hepatitis
C NS3/4A inhibitors was identified by
introducing a novel spirocyclic
proline–P2 surrogate onto the P2–P4 macrocyclic core
of MK-5172 (grazoprevir). The potency profile of new analogues showed
excellent pan-genotypic activity for most compounds. The potency evaluation
included the most difficult genotype 3a (EC<sub>50</sub> values ≤10
nM) and other key genotype 1b mutants. Molecular modeling was used
to design new target compounds and rationalize our results. A synthetic
approach based on the Julia–Kocienski olefination and macrolactamization
to assemble the P2–P4 macrocyclic core containing the novel
spirocyclic proline–P2 moiety is presented as well