Intestinally Targeted Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitors Robustly Suppress Postprandial Triglycerides

被引：26

作者：

Serrano-Wu, Michael H. ^{[1
]}

Coppola, Gary M. ^{[1
]}

Gong, Yongjin ^{[1
]}

Neubert, Alan D. ^{[1
]}

Chatelain, Ricardo ^{[2
]}

Clairmont, Kevin B. ^{[2
]}

Commerford, Renee ^{[2
]}

Cosker, Theresa ^{[3
]}

Daniels, Thomas ^{[2
]}

Hou, Ying ^{[1
]}

Jain, Monish ^{[3
]}

Juedes, Marlene ^{[4
]}

Li, Lisha ^{[2
]}

Mullarkey, Tara ^{[2
]}

Rocheford, Erik ^{[2
]}

Sung, Moo Je ^{[1
]}

Tyler, Andrew ^{[2
]}

Yang, Qing ^{[2
]}

Yoon, Taeyoung ^{[1
]}

Hubbard, Brian K. ^{[2
]}

机构：

[1] Novartis Inst Biomed Res, Dept Global Discovery Chem, Cambridge, MA 02139 USA

[2] Novartis Inst Biomed Res, Dept Cardiovasc & Metab, Cambridge, MA 02139 USA

[3] Novartis Inst Biomed Res, Dept Metab & Pharmacokinet, Cambridge, MA 02139 USA

[4] Novartis Inst Biomed Res, Dept Translat Sci, Cambridge, MA 02139 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2012年 / 3卷 / 05期

关键词：

DGAT1; triglyceride synthesis; efflux; OBESITY; POTENT; IDENTIFICATION; RESISTANCE; DISCOVERY; GENE;

D O I：

10.1021/ml3000512

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：411 / 415

页数：5

共 50 条

[31] Identification and characterization of an efficient acyl-CoA: diacylglycerol acyltransferase 1 (DGAT1) gene from the microalga Chlorella ellipsoidea
Xuejie Guo
Chengming Fan
Yuhong Chen
Jingqiao Wang
Weibo Yin
Richard R. C. Wang
Zanmin Hu
BMC Plant Biology, 17
[32] Synthesis and biological evaluation of novel thienopyrimidine derivatives as diacylglycerol acyltransferase 1 (DGAT-1) inhibitors
Hong, Dong Jin
Jung, Seung Hyun
Kim, Jisook
Jung, Danbee
Ahn, Young Gil
Suh, Kwee Hyun
Min, Kyung Hoon
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2020, 35 (01) : 227 - 234
[33] In vivo efficacy of acyl CoA: Diacylglycerol acyltransferase (DGAT) 1 inhibition in rodent models of postprandial hyperlipidemia
King, Andrew J.
Segreti, Jason A.
Larson, Kelly J.
Souers, Andrew J.
Kym, Philip R.
Reilly, Regina M.
Collins, Christine A.
Voorbach, Martin J.
Zhao, Gang
Mittelstadt, Scott W.
Cox, Bryan F.
EUROPEAN JOURNAL OF PHARMACOLOGY, 2010, 637 (1-3) : 155 - 161
[34] Cardiomyocyte-specific Loss of Diacylglycerol Acyltransferase 1 (DGAT1) Reproduces the Abnormalities in Lipids Found in Severe Heart Failure
Liu, Li
Trent, Chad M.
Fang, Xiang
Son, Ni-Huiping
Jiang, HongFeng
Blaner, William S.
Hu, Yunying
Yin, Yu-Xin
Farese, Robert V., Jr.
Homma, Shunichi
Turnbull, Andrew V.
Eriksson, Jan W.
Hu, Shi-Lian
Ginsberg, Henry N.
Huang, Li-Shin
Goldberg, Ira J.
JOURNAL OF BIOLOGICAL CHEMISTRY, 2014, 289 (43) : 29881 - 29891
[35] Identification of a single nucleotide polymorphism at intron 16 of the caprine acyl-coenzyme A:: Diacylglycerol acyltransferase 1 (DGAT1) gene
Angiolillo, Antonella
Amills, Marcel
Urrutia, Baltasar
Domenech, Anna
Sastre, Yolanda
Badaoui, Bouabid
Jordana, Jordi
JOURNAL OF DAIRY RESEARCH, 2007, 74 (01) : 47 - 51
[36] Evidence That Diacylglycerol Acyltransferase 1 (DGAT1) Has Dual Membrane Topology in the Endoplasmic Reticulum of HepG2 Cells
Wurie, Haja R.
Buckett, Linda
Zammit, Victor A.
JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (42) : 36238 - 36247
[37] Identification and characterization of an efficient acyl-CoA: diacylglycerol acyltransferase 1 (DGAT1) gene from the microalga Chlorella ellipsoidea
Guo, Xuejie
Fan, Chengming
Chen, Yuhong
Wang, Jingqiao
Yin, Weibo
Wang, Richard R. C.
Hu, Zanmin
BMC PLANT BIOLOGY, 2017, 17
[38] Role of diacylglycerol O-acyltransferase 1 (DGAT1) in lipolysis and autophagy of adipose tissue from ketotic dairy cows
Xu, Qiushi
Fan, Yunhui
Mauck, John
Loor, Juan J.
Sun, Xudong
Jia, Hongdou
Li, Xinwei
Xu, Chuang
JOURNAL OF DAIRY SCIENCE, 2024, 107 (07) : 5150 - 5161
[39] Design and Optimization of Pyrazinecarboxamide-Based Inhibitors of Diacylglycerol Acyltransferase 1 (DGAT1) Leading to a Clinical Candidate Dimethylpyrazinecarboxamide Phenylcyclohexylacetic Acid (AZD7687)
Barlind, Jonas G.
Bauer, Udo A.
Birch, Alan M.
Birtles, Susan
Buckett, Linda K.
Butlin, Roger J.
Davies, Robert D. M.
Eriksson, Jan W.
Hammond, Clare D.
Hovland, Ragnar
Johannesson, Petra
Johansson, Magnus J.
Kemmitt, Paul D.
Lindmark, Bo T.
Gutierrez, Pablo Morentin
Noeske, Tobias A.
Nordin, Andreas
O'Donnell, Charles J.
Petersson, Annika U.
Redzic, Alma
Turnbull, Andrew V.
Vinblad, Johanna
JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (23) : 10610 - 10629
[40] Discovery of pyrrolopyridazines as novel DGAT1 inhibitors
Fox, Brian M.
Iio, Kiyosei
Li, Kexue
Inaba, Takashi
Jackson, Simon
Choi, Rebekah
Sagawa, Shoichi
Shan, Bei
Tanaka, Masahiro
Yoshida, Atsuhito
Kayser, Frank
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2009, 237

← 1 2 3 4 5 →