title: Intestinally Targeted Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitors Robustly Suppress Postprandial Triglycerides.
abstract: High DGAT1 expression levels in the small intestine highlight the critical role this enzyme plays in nutrient absorption. Identification of inhibitors which predominantly inhibit DGAT1 in the gut is an attractive drug discovery strategy with anticipated benefits of reduced systemic toxicity. In this report we describe our discovery and optimization of DGAT1 inhibitors whose plasma exposure is minimized by the action of transporters, including the P-glycoprotein transporter. The impact of this unique absorption profile on efficacy in rat and dog efficacy models is presented.
authors.affiliation: Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Serrano-Wu
authors.affiliation: Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
authors.forename: Gary M
authors.initials: GM
authors.lastname: Coppola
authors.affiliation: Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
authors.forename: Yongjin
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Neubert
authors.affiliation: Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Chatelain
authors.affiliation: Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Clairmont
authors.affiliation: Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
authors.forename: Renee
authors.initials: R
authors.lastname: Commerford
authors.affiliation: Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
authors.forename: Theresa
authors.initials: T
authors.lastname: Cosker
authors.affiliation: Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Daniels
authors.affiliation: Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
authors.forename: Monish
authors.initials: M
authors.lastname: Jain
authors.affiliation: Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
authors.forename: Marlene
authors.initials: M
authors.lastname: Juedes
authors.affiliation: Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
authors.forename: Lisha
authors.initials: L
authors.lastname: Li
authors.affiliation: Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
authors.forename: Tara
authors.initials: T
authors.lastname: Mullarkey
authors.affiliation: Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
authors.forename: Erik
authors.initials: E
authors.lastname: Rocheford
authors.affiliation: Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
authors.forename: Moo Je
authors.initials: MJ
authors.lastname: Sung
authors.affiliation: Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Tyler
authors.affiliation: Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
authors.forename: Taeyoung
authors.initials: T
authors.lastname: Yoon
authors.affiliation: Departments of Global Discovery Chemistry, Cardiovascular and Metabolism, Metabolism and Pharmacokinetics, and Translational Sciences, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge Massachusetts 02139, United States.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Hubbard
keywords: DGAT1; efflux; triglyceride synthesis