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

[41] Diacylglycerol acyltransferase (DGAT) activity in relation to muscle fat content and DGAT1 genotype in two different breeds of Bos Taurus (short communication)
Sorensen, Brent
Kuehn, Christa
Teuscher, Friedrich
Schneider, Falk
Weselake, Randall
Wegner, Jochen
ARCHIV FUR TIERZUCHT-ARCHIVES OF ANIMAL BREEDING, 2006, 49 (04): : 351 - 356
[42] Discovery of pyrrolopyridazines as novel DGAT1 inhibitors
Fox, Brian M.
Iio, Kiyosei
Li, Kexue
Choi, Rebeka
Inaba, Takashi
Jackson, Simon
Sagawa, Shoichi
Shan, Bei
Tanaka, Masahiro
Yoshida, Atsuhito
Kayser, Frank
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (20) : 6030 - 6033
[43] Structural characterisation of the acyl CoA: diacylglycerol acyltransferase 1 (DGAT1) gene and association studies with milk traits in Assaf sheep breed
Dervishi, E.
Serrano, M.
Joy, M.
Sarto, P.
Somera, A.
Gonzalez-Calvo, L.
Berzal-Herranz, B.
Molino, F.
Martinez-Royo, A.
Calvo, J. H.
SMALL RUMINANT RESEARCH, 2015, 131 : 78 - 84
[44] Growth hormone (GH), prolactin (PRL), and diacylglycerol acyltransferase (DGAT1) gene polymorphisms in Turkish native cattle breeds
Unal, Emel Ozkan
Kepenek, Eda Seyma
Dinc, Havva
Ozer, Fusun
Sonmez, Gizem
Togan, Inci Zehra
Soysal, Mehmet Ihsan
TURKISH JOURNAL OF ZOOLOGY, 2015, 39 (05) : 734 - 748
[45] Concerted elevation of acyl-coenzyme A:diacylglycerol acyltransferase (DGAT) activity through independent stimulation of mRNA expression of DGAT1 and DGAT2 by carbohydrate and insulin
Meegalla, RL
Billheimer, JT
Cheng, D
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2002, 298 (03) : 317 - 323
[46] Exclusion of the acyl CoA:diacylglycerol acyltransferase 1 gene (DGAT1) as a candidate for a fatty acid composition QTL on porcine chromosome 4
Mercadé, A
Sánchez, A
Folch, JM
JOURNAL OF ANIMAL BREEDING AND GENETICS, 2005, 122 (03) : 161 - 164
[47] Directed evolution of acyl-CoA:diacylglycerol acyltransferase: Development and characterization of Brassica napus DGAT1 mutagenized libraries
Siloto, Rodrigo M. P.
Truksa, Martin
Brownfield, Disa
Good, Allen G.
Weselake, Randall J.
PLANT PHYSIOLOGY AND BIOCHEMISTRY, 2009, 47 (06) : 456 - 461
[48] In silico characterization and expression profiling of the diacylglycerol acyltransferase gene family (DGAT1, DGAT2, DGAT3 and WS/DGAT) from oil palm, Elaeis guineensis
Rosli, Rozana
Chan, Pek-Lan
Chan, Kuang-Lim
Amiruddin, Nadzirah
Low, Eng-Ti Leslie
Singh, Rajinder
Harwood, John L.
Murphy, Denis J.
PLANT SCIENCE, 2018, 275 : 84 - 96
[49] The Role of Diacylglycerol Acyltransferase (DGAT) 1 and 2 in Cardiac Metabolism and Function
Nathan D. Roe
Michal K. Handzlik
Tao Li
Rong Tian
Scientific Reports, 8
[50] Frequency and effect of the bovine acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) K232A polymorphism in Swedish dairy cattle
Naslund, J.
Fikse, W. F.
Pielberg, G. R.
Lunden, A.
JOURNAL OF DAIRY SCIENCE, 2008, 91 (05) : 2127 - 2134

← 1 2 3 4 5 →