Validation of diacyl glycerolacyltransferase I as a novel target for the treatment of obesity and dyslipidemia using a potent and selective small molecule inhibitor.
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.
Zhao
Gang
G
Metabolic Disease Research, Abbott Laboratories, Abbott Park, IL 60064, USA.
Souers
Andrew J
AJ
Voorbach
Martin
M
Falls
H Doug
HD
Droz
Brian
B
Brodjian
Sevan
S
Lau
Yau Yi
YY
Iyengar
Rajesh R
RR
Gao
Ju
J
Judd
Andrew S
AS
Wagaw
Seble H
SH
Ravn
Matthew M
MM
Engstrom
Kenneth M
KM
Lynch
John K
JK
Mulhern
Mathew M
MM
Freeman
Jennifer
J
Dayton
Brian D
BD
Wang
Xiaojun
X
Grihalde
Nelson
N
Fry
Dennis
D
Beno
David W A
DW
Marsh
Kennan C
KC
Su
Zhi
Z
Diaz
Gilbert J
GJ
Collins
Christine A
CA
Sham
Hing
H
Reilly
Regina M
RM
Brune
Michael E
ME
Kym
Philip R
PR
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
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