title: Novel Quinoline-Based P2-P4 Macrocyclic Derivatives As Pan-Genotypic HCV NS3/4a Protease Inhibitors.
abstract: We have previously reported the discovery of our P2-P4 macrocyclic HCV NS3/4a protease inhibitor MK-5172, which in combination with the NS5a inhibitor MK-8742 recently received a breakthrough therapy designation from the US FDA for treatment of chronic HCV infection. Our goal for the next generation NS3/4a inhibitor was to achieve pan-genotypic activity while retaining the pharmacokinetic profile of MK-5172. One of the areas for follow-up investigation involved replacement of the quinoxaline moiety in MK-5172 with a quinoline and studying the effect of substitution at 4-position of the quinoline. The rationale for this effort was based on molecular modeling, which indicated that such modifications would improve interactions with the S2 subsite, in particular with D79. We wish to report herein the discovery of highly potent inhibitors with pan-genotypic activity and an improved profile over MK-5172, especially against gt-3a and A156 mutants.
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Unmesh
authors.initials: U
authors.lastname: Shah
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Charles
authors.initials: C
authors.lastname: Jayne
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Samuel
authors.initials: S
authors.lastname: Chackalamannil
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Francisco
authors.initials: F
authors.lastname: Velázquez
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Zhuyan
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Alexei
authors.initials: A
authors.lastname: Buevich
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: John A
authors.initials: JA
authors.lastname: Howe
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Chase
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Aileen
authors.initials: A
authors.lastname: Soriano
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Sony
authors.initials: S
authors.lastname: Agrawal
authors.affiliation: Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Rudd
authors.affiliation: Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: John A
authors.initials: JA
authors.lastname: McCauley
authors.affiliation: Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Liverton
authors.affiliation: Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Romano
authors.affiliation: Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Bush
authors.affiliation: Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.affiliation: Merck Research Laboratories , Kirkland, Quebec H9H3L1, Canada.
authors.forename: Christiane
authors.initials: C
authors.lastname: Grisé-Bard
authors.affiliation: Merck Research Laboratories , Kirkland, Quebec H9H3L1, Canada.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Brochu
authors.affiliation: Merck Research Laboratories , Kirkland, Quebec H9H3L1, Canada.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Charron
authors.affiliation: Merck Research Laboratories , Kirkland, Quebec H9H3L1, Canada.
authors.forename: Virender
authors.initials: V
authors.lastname: Aulakh
authors.affiliation: Merck Research Laboratories , Kirkland, Quebec H9H3L1, Canada.
authors.forename: Benoit
authors.initials: B
authors.lastname: Bachand
authors.affiliation: Merck Research Laboratories , Kirkland, Quebec H9H3L1, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Beaulieu
authors.affiliation: Merck Research Laboratories , Kirkland, Quebec H9H3L1, Canada.
authors.forename: Helmi
authors.initials: H
authors.lastname: Zaghdane
authors.affiliation: Merck Research Laboratories , Kirkland, Quebec H9H3L1, Canada.
authors.forename: Sathesh
authors.initials: S
authors.lastname: Bhat
authors.affiliation: Merck Research Laboratories , Kirkland, Quebec H9H3L1, Canada.
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Han
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Ian W
authors.initials: IW
authors.lastname: Davies
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Weber
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Venkatraman
keywords: Antiviral; HCV; NS3/4a; genotype 3a; macrocycle; pan-genotypic