title: Discovery and Pharmacology of a Novel Class of Diacylglycerol Acyltransferase 2 Inhibitors.
abstract: DGAT2 plays a critical role in hepatic triglyceride production, and data suggests that inhibition of DGAT2 could prove to be beneficial in treating a number of disease states. This article documents the discovery and optimization of a selective small molecule inhibitor of DGAT2 as well as pharmacological proof of biology in a mouse model of triglyceride production.
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Imbriglio
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Dong-Ming
authors.initials: DM
authors.lastname: Shen
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Rui
authors.initials: R
authors.lastname: Liang
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Ken
authors.initials: K
authors.lastname: Marby
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Ming
authors.initials: M
authors.lastname: You
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Hye Won
authors.initials: HW
authors.lastname: Youm
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Clare
authors.initials: C
authors.lastname: London
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Jim
authors.initials: J
authors.lastname: Tata
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Andreas
authors.initials: A
authors.lastname: Verras
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Margarita
authors.initials: M
authors.lastname: Garcia-Calvo
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Xuelei
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: George H
authors.initials: GH
authors.lastname: Addona
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Dave G
authors.initials: DG
authors.lastname: McLaren
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Timothy
authors.initials: T
authors.lastname: He
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Beth
authors.initials: B
authors.lastname: Murphy
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Dan E
authors.initials: DE
authors.lastname: Metzger
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Gino
authors.initials: G
authors.lastname: Salituro
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Diana
authors.initials: D
authors.lastname: Deckman
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Jin
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Stout
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Sheng-Ping
authors.initials: SP
authors.lastname: Wang
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Larissa
authors.initials: L
authors.lastname: Wilsie
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Oksana
authors.initials: O
authors.lastname: Palyha
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Seongah
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Hubbard
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Previs
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Shirly
authors.initials: S
authors.lastname: Pinto
authors.affiliation: Department of Discovery Chemistry, ‡Chemistry Modeling, and Informatics, §In Vitro Pharmacology, ∥In Vivo Pharmacology, ⊥Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, #Basic Pharmaceutical Sciences, and ○Atherosclerosis, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Taggart
mesh_terms: D000818:Animals; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014280:Triglycerides / Q000097:blood / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D007546:Isoquinolines; D014280:Triglycerides; C494885:DGAT2 protein, human; D051048:Diacylglycerol O-Acyltransferase