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Design and Synthesis of P2-P4 Macrocycles Containing a Unique Spirocyclic Proline: A New Class of HCV NS3/4A Inhibitors.


ABSTRACT: 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 (EC50 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.

SUBMITTER: Velazquez F 

PROVIDER: S-EPMC5150670 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Design and Synthesis of P2-P4 Macrocycles Containing a Unique Spirocyclic Proline: A New Class of HCV NS3/4A Inhibitors.

Velázquez Francisco F   Chelliah Mariappan M   Clasby Martin M   Guo Zhuyan Z   Howe John J   Miller Randy R   Neelamkavil Santhosh S   Shah Unmesh U   Soriano Aileen A   Xia Yan Y   Venkatraman Srikanth S   Chackalamannil Samuel S   Davies Ian W IW  

ACS medicinal chemistry letters 20161017 12


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  ...[more]

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