title: Discovery of Benzimidazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys.
abstract: We report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Hoyt
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Min K
authors.initials: MK
authors.lastname: Park
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Clare
authors.initials: C
authors.lastname: London
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Jim
authors.initials: J
authors.lastname: Tata
authors.affiliation: Merck Research Laboratories , Newhouse, Lanarkshire ML1 5SH, United Kingdom.
authors.forename: D Jonathan
authors.initials: DJ
authors.lastname: Bennett
authors.affiliation: Merck Research Laboratories , Newhouse, Lanarkshire ML1 5SH, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Cooke
authors.affiliation: Merck Research Laboratories , Newhouse, Lanarkshire ML1 5SH, United Kingdom.
authors.forename: Jiaqiang
authors.initials: J
authors.lastname: Cai
authors.affiliation: Merck Research Laboratories , Newhouse, Lanarkshire ML1 5SH, United Kingdom.
authors.forename: Emma
authors.initials: E
authors.lastname: Carswell
authors.affiliation: Merck Research Laboratories , Newhouse, Lanarkshire ML1 5SH, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Robinson
authors.affiliation: Merck Research Laboratories , Newhouse, Lanarkshire ML1 5SH, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: MacLean
authors.affiliation: Merck Research Laboratories , Newhouse, Lanarkshire ML1 5SH, United Kingdom.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Brown
authors.affiliation: Merck Research Laboratories , Newhouse, Lanarkshire ML1 5SH, United Kingdom.
authors.forename: Simone
authors.initials: S
authors.lastname: Belshaw
authors.affiliation: Merck Research Laboratories , Newhouse, Lanarkshire ML1 5SH, United Kingdom.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Clarkson
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Kun
authors.initials: K
authors.lastname: Liu
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Gui-Bai
authors.initials: GB
authors.lastname: Liang
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Mary
authors.initials: M
authors.lastname: Struthers
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Doris
authors.initials: D
authors.lastname: Cully
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Tom
authors.initials: T
authors.lastname: Wisniewski
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Ning
authors.initials: N
authors.lastname: Ren
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Charlene
authors.initials: C
authors.lastname: Bopp
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sok
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Tian-Quan
authors.initials: TQ
authors.lastname: Cai
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Sloan
authors.initials: S
authors.lastname: Stribling
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Lee-Yuh
authors.initials: LY
authors.lastname: Pai
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Xiuying
authors.initials: X
authors.lastname: Ma
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Joe
authors.initials: J
authors.lastname: Metzger
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Andreas
authors.initials: A
authors.lastname: Verras
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: McMasters
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Elaine
authors.initials: E
authors.lastname: Tung
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Gino
authors.initials: G
authors.lastname: Salituro
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Nicole
authors.initials: N
authors.lastname: Buist
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Jeff
authors.initials: J
authors.lastname: Kuethe
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Nelo
authors.initials: N
authors.lastname: Rivera
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Joe
authors.initials: J
authors.lastname: Clemas
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Gaochao
authors.initials: G
authors.lastname: Zhou
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Jack
authors.initials: J
authors.lastname: Gibson
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Carrie Ann
authors.initials: CA
authors.lastname: Maxwell
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Mike
authors.initials: M
authors.lastname: Lassman
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Theresa
authors.initials: T
authors.lastname: McLaughlin
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Jose
authors.initials: J
authors.lastname: Castro-Perez
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Daphne
authors.initials: D
authors.lastname: Szeto
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Gail
authors.initials: G
authors.lastname: Forrest
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Hajdu
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Rosenbach
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Amjad
authors.initials: A
authors.lastname: Ali
keywords: CYP11B2; aldosterone synthase; hypertension