title: Microscale High-Throughput Experimentation as an Enabling Technology in Drug Discovery: Application in the Discovery of (Piperidinyl)pyridinyl-1H-benzimidazole Diacylglycerol Acyltransferase 1 Inhibitors.
abstract: Miniaturization and parallel processing play an important role in the evolution of many technologies. We demonstrate the application of miniaturized high-throughput experimentation methods to resolve synthetic chemistry challenges on the frontlines of a lead optimization effort to develop diacylglycerol acyltransferase (DGAT1) inhibitors. Reactions were performed on ∼1 mg scale using glass microvials providing a miniaturized high-throughput experimentation capability that was used to study a challenging SNAr reaction. The availability of robust synthetic chemistry conditions discovered in these miniaturized investigations enabled the development of structure-activity relationships that ultimately led to the discovery of soluble, selective, and potent inhibitors of DGAT1.
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Tim
authors.identifier: 0000-0001-5407-0643
authors.initials: T
authors.lastname: Cernak
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Gesmundo
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Dykstra
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Zhicai
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Zhi-Cai
authors.initials: ZC
authors.lastname: Shi
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Petr
authors.initials: P
authors.lastname: Vachal
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Donald
authors.initials: D
authors.lastname: Sperbeck
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Shuwen
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Beth Ann
authors.initials: BA
authors.lastname: Murphy
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Lisa
authors.initials: L
authors.lastname: Sonatore
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Williams
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Maria
authors.initials: M
authors.lastname: Madeira
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Andreas
authors.initials: A
authors.lastname: Verras
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Maud
authors.initials: M
authors.lastname: Reiter
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Claire Heechoon
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: James
authors.initials: J
authors.lastname: Cuff
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Edward C
authors.identifier: 0000-0001-8178-9186
authors.initials: EC
authors.lastname: Sherer
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kuethe
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Goble
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Perrotto
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Shirly
authors.initials: S
authors.lastname: Pinto
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Dong-Ming
authors.initials: DM
authors.lastname: Shen
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Ravi
authors.initials: R
authors.lastname: Nargund
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: James
authors.initials: J
authors.lastname: Balkovec
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: DeVita
authors.affiliation: Department of Discovery Chemistry, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.
authors.forename: Spencer D
authors.initials: SD
authors.lastname: Dreher
mesh_terms: D002853:Chromatography, Liquid; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013058:Mass Spectrometry; D066244:Proton Magnetic Resonance Spectroscopy
chemical_list: D004791:Enzyme Inhibitors; D051048:Diacylglycerol O-Acyltransferase