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

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

  • ACS Med Chem Lett. 2016 Oct 17;7(12):1173-1178. doi: 10.1021/acsmedchemlett.6b00321.
Francisco Velázquez 1,  Mariappan Chelliah 1,  Martin Clasby 1,  Zhuyan Guo 1,  John Howe 1,  Randy Miller 1,  Santhosh Neelamkavil 1,  Unmesh Shah 1,  Aileen Soriano 1,  Yan Xia 1,  Srikanth Venkatraman 1,  Samuel Chackalamannil 1,  Ian W Davies 1
Affiliations

Affiliation

  • 1 Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
PMID: 27994759 DOI: 10.1021/acsmedchemlett.6b00321
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.

Keywords

HCV; HCV NS3/4A; Hepatitis C; MK-5172; MK-8831; antivirals.

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