title: Potent DGAT1 Inhibitors in the Benzimidazole Class with a Pyridyl-oxy-cyclohexanecarboxylic Acid Moiety.
abstract: We report the design and synthesis of a series of novel DGAT1 inhibitors in the benzimidazole class with a pyridyl-oxy-cyclohexanecarboxylic acid moiety. In particular, compound 11A is a potent DGAT1 inhibitor with excellent selectivity against ACAT1. Compound 11A significantly reduces triglyceride excursion in lipid tolerance tests (LTT) in both mice and dogs at low plasma exposure. An in vivo study in mice with des-fluoro analogue 10A indicates that this series of compounds appears to distribute in intestine preferentially over plasma. The propensity to target intestine over plasma could be advantageous in reducing potential side effects since lower circulating levels of drug are required for efficacy. However, in the preclinical species, compound 11A undergoes cis/trans epimerization in vivo, which could complicate further development due to the presence of an active metabolite.
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Shuwen
authors.initials: S
authors.lastname: He
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Qingmei
authors.initials: Q
authors.lastname: Hong
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Lai
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Zhicai
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: David W
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Pauline C
authors.initials: PC
authors.lastname: Ting
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Kuethe
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Ginger X
authors.initials: GX
authors.lastname: Yang
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Tianying
authors.initials: T
authors.lastname: Jian
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Deodial
authors.initials: D
authors.lastname: Guiadeen
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Arto D
authors.initials: AD
authors.lastname: Krikorian
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Sperbeck
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Sonatore
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Judyann
authors.initials: J
authors.lastname: Wiltsie
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Christine C
authors.initials: CC
authors.lastname: Chung
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Jack T
authors.initials: JT
authors.lastname: Gibson
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: JeanMarie
authors.initials: J
authors.lastname: Lisnock
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Murphy
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Judith N
authors.initials: JN
authors.lastname: Gorski
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Jinqi
authors.initials: J
authors.lastname: Liu
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Dunlu
authors.initials: D
authors.lastname: Chen
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Chen
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Wolff
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Sharon X
authors.initials: SX
authors.lastname: Tong
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Maria
authors.initials: M
authors.lastname: Madeira
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Bindhu V
authors.initials: BV
authors.lastname: Karanam
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Dong-Ming
authors.initials: DM
authors.lastname: Shen
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: James M
authors.initials: JM
authors.lastname: Balkovec
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Shirly
authors.initials: S
authors.lastname: Pinto
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Ravi P
authors.initials: RP
authors.lastname: Nargund
authors.affiliation: Discovery and Preclinical Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: DeVita
keywords: ACAT1; DGAT1; benzimidazole; cyclohexanecarboxylic acid; epimerization; inhibitor; lipid tolerance test; metabolite