title: Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor.
abstract: We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Santhosh F
authors.initials: SF
authors.lastname: Neelamkavil
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 , Kenilworth, New Jersey 07033, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bara
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Chad
authors.initials: C
authors.lastname: Bennett
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Sathesh
authors.initials: S
authors.lastname: Bhat
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Dipshikha
authors.initials: D
authors.lastname: Biswas
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Linda
authors.initials: L
authors.lastname: Brockunier
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Nicole
authors.initials: N
authors.lastname: Buist
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Duane
authors.initials: D
authors.lastname: Burnette
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Cartwright
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: Robert
authors.initials: R
authors.lastname: Chase
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Mariappan
authors.initials: M
authors.lastname: Chelliah
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Austin
authors.initials: A
authors.lastname: Chen
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Martin
authors.initials: M
authors.lastname: Clasby
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Colandrea
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: Keith
authors.initials: K
authors.lastname: Eagen
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: Yongxin
authors.initials: Y
authors.lastname: Han
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: John
authors.initials: J
authors.lastname: Howe
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: Hubert
authors.initials: H
authors.lastname: Josien
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Stacia
authors.initials: S
authors.lastname: Kargman
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Karen
authors.initials: K
authors.lastname: Marcantonio
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Shouwu
authors.initials: S
authors.lastname: Miao
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Randy
authors.initials: R
authors.lastname: Miller
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Nolting
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Patrick
authors.initials: P
authors.lastname: Pinto
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Murali
authors.initials: M
authors.lastname: Rajagopalan
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Rebecca T
authors.initials: RT
authors.lastname: Ruck
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: Aileen
authors.initials: A
authors.lastname: Soriano
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Donald
authors.initials: D
authors.lastname: Sperbeck
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Francisco
authors.initials: F
authors.lastname: Velazquez
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Jin
authors.initials: J
authors.lastname: Wu
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Venkatraman
keywords: Antiviral; HCV; MK-5172; MK-8831; NS3/4a; genotype 3a; macrocycle; pan-genotypic
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