title: Discovery of a Potent and Selective DGAT1 Inhibitor with a Piperidinyl-oxy-cyclohexanecarboxylic Acid Moiety.
abstract: We report the discovery of a novel series of DGAT1 inhibitors in the benzimidazole class with a piperdinyl-oxy-cyclohexanecarboxylic acid moiety. This novel series possesses significantly improved selectivity against the A2A receptor, no ACAT1 off-target activity at 10 μM, and higher aqueous solubility and free fraction in plasma as compared to the previously reported pyridyl-oxy-cyclohexanecarboxylic acid series. In particular, 5B was shown to possess an excellent selectivity profile by screening it against a panel of more than 100 biological targets. Compound 5B significantly reduces lipid excursion in LTT in mouse and rat, demonstrates DGAT1 mediated reduction of food intake and body weight in mice, is negative in a 3-strain Ames test, and appears to distribute preferentially in the liver and the intestine in mice. We believe this lead series possesses significant potential to identify optimized compounds for clinical development.
authors.affiliation: Early Development and Discovery 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: Early Development and Discovery 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: Early Development and Discovery 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: Early Development and Discovery Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: David X
authors.initials: DX
authors.lastname: Yang
authors.affiliation: Early Development and Discovery 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: Early Development and Discovery 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: Early Development and Discovery Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Cernak
authors.affiliation: Early Development and Discovery Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Dykstra
authors.affiliation: Early Development and Discovery 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: Early Development and Discovery 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: Early Development and Discovery 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: Early Development and Discovery 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: Early Development and Discovery 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: Early Development and Discovery 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: Early Development and Discovery 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: Early Development and Discovery 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: Early Development and Discovery 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: Early Development and Discovery 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: Early Development and Discovery 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: Early Development and Discovery 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: Early Development and Discovery 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: Early Development and Discovery 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: Early Development and Discovery 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: Early Development and Discovery Sciences, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Jianying
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Early Development and Discovery 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: Early Development and Discovery 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: Early Development and Discovery 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: Early Development and Discovery 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: Early Development and Discovery 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: Early Development and Discovery 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: Early Development and Discovery 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: Early Development and Discovery 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: Early Development and Discovery 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: A2A receptor; ACAT1; Ames test; DGAT1; benzimidazole; cyclohexanecarboxylic acid; epimerization; inhibitor; lipid tolerance test; metabolite; skin