title: 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 (EC50values ≤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.
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Francisco
authors.initials: F
authors.lastname: Velázquez
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Mariappan
authors.initials: M
authors.lastname: Chelliah
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Martin
authors.initials: M
authors.lastname: Clasby
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Zhuyan
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: John
authors.initials: J
authors.lastname: Howe
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Randy
authors.initials: R
authors.lastname: Miller
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Santhosh
authors.initials: S
authors.lastname: Neelamkavil
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Unmesh
authors.initials: U
authors.lastname: Shah
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Aileen
authors.initials: A
authors.lastname: Soriano
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Venkatraman
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Samuel
authors.initials: S
authors.lastname: Chackalamannil
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Ian W
authors.initials: IW
authors.lastname: Davies
keywords: HCV; HCV NS3/4A; Hepatitis C; MK-5172; MK-8831; antivirals