title: Validation of diacyl glycerolacyltransferase I as a novel target for the treatment of obesity and dyslipidemia using a potent and selective small molecule inhibitor.
abstract: A highly potent and selective DGAT-1 inhibitor was identified and used in rodent models of obesity and postprandial chylomicron excursion to validate DGAT-1 inhibition as a novel approach for the treatment of metabolic diseases. Specifically, compound 4a conferred weight loss and a reduction in liver triglycerides when dosed chronically in DIO mice and depleted serum triglycerides following a lipid challenge in a dose-dependent manner, thus, reproducing major phenotypical characteristics of DGAT-1(-/-) mice.
authors.affiliation: Metabolic Disease Research, Abbott Laboratories, Abbott Park, IL 60064, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Souers
authors.forename: Martin
authors.initials: M
authors.lastname: Voorbach
authors.forename: H Doug
authors.initials: HD
authors.lastname: Falls
authors.forename: Brian
authors.initials: B
authors.lastname: Droz
authors.forename: Sevan
authors.initials: S
authors.lastname: Brodjian
authors.forename: Yau Yi
authors.initials: YY
authors.lastname: Lau
authors.forename: Rajesh R
authors.initials: RR
authors.lastname: Iyengar
authors.forename: Ju
authors.initials: J
authors.lastname: Gao
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Judd
authors.forename: Seble H
authors.initials: SH
authors.lastname: Wagaw
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ravn
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Engstrom
authors.forename: John K
authors.initials: JK
authors.lastname: Lynch
authors.forename: Mathew M
authors.initials: MM
authors.lastname: Mulhern
authors.forename: Jennifer
authors.initials: J
authors.lastname: Freeman
authors.forename: Brian D
authors.initials: BD
authors.lastname: Dayton
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Wang
authors.forename: Nelson
authors.initials: N
authors.lastname: Grihalde
authors.forename: Dennis
authors.initials: D
authors.lastname: Fry
authors.forename: David W A
authors.initials: DW
authors.lastname: Beno
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Zhi
authors.initials: Z
authors.lastname: Su
authors.forename: Gilbert J
authors.initials: GJ
authors.lastname: Diaz
authors.forename: Christine A
authors.initials: CA
authors.lastname: Collins
authors.forename: Hing
authors.initials: H
authors.lastname: Sham
authors.forename: Regina M
authors.initials: RM
authors.lastname: Reilly
authors.forename: Michael E
authors.initials: ME
authors.lastname: Brune
authors.forename: Philip R
authors.initials: PR
authors.lastname: Kym
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D003508:Cycloheptanes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics; D004435:Eating / Q000187:drug effects; D006801:Humans; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics; D007651:Keto Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015431:Weight Loss
chemical_list: D019440:Anti-Obesity Agents; D001713:Biphenyl Compounds; D003508:Cycloheptanes; D000960:Hypolipidemic Agents; D007527:Isoenzymes; D007651:Keto Acids; D014280:Triglycerides; D014508:Urea; C494881:DGAT1 protein, human; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase