Design of small molecule inhibitors of acetyl-CoA carboxylase 1 and 2 showing reduction of hepatic malonyl-CoA levels in vivo in obese Zucker rats

被引：38

作者：

Bengtsson, Christoffer ^{[1
]}

Blaho, Stefan ^{[1
]}

Saitton, David Blomberg ^{[1
]}

Brickmann, Kay ^{[1
]}

Broddefalk, Johan ^{[1
]}

Davidsson, Ojvind ^{[1
]}

Drmota, Tomas ^{[1
]}

Folmer, Rutger ^{[1
]}

Hallberg, Kenth ^{[1
]}

Hallen, Stefan ^{[1
]}

Hovland, Ragnar ^{[1
]}

Isin, Emre ^{[1
]}

Johannesson, Petra ^{[1
]}

Kull, Bengt ^{[1
]}

Larsson, Lars-Olof ^{[1
]}

Lofgren, Lars ^{[1
]}

Nilsson, Kristina E. ^{[1
]}

Noeske, Tobias ^{[1
]}

Oakes, Nick ^{[1
]}

Plowright, Alleyn T. ^{[1
]}

Schnecke, Volker ^{[1
]}

Stahlberg, Pernilla ^{[1
]}

Sorme, Pernilla ^{[1
]}

Wan, Hong ^{[1
]}

Wellner, Eric ^{[1
]}

Oster, Linda ^{[1
]}

机构：

[1] AstraZeneca Res & Dev, S-43183 Molndal, Sweden

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2011年 / 19卷 / 10期

关键词：

Acetyl-CoA carboxylase; Malonyl-CoA; Ligand lipophilicity efficiency; Quinoline; FATTY-ACID OXIDATION; INSULIN-RESISTANCE; DRUG DISCOVERY; MUTANT MICE; COENZYME; DENSITY; DERIVATIVES; ABSORPTION; KNOCKOUT; TISSUE;

D O I：

10.1016/j.bmc.2011.04.014

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Inhibition of acetyl-CoA carboxylases has the potential for modulating long chain fatty acid biosynthesis and mitochondrial fatty acid oxidation. Hybridization of weak inhibitors of ACC2 provided a novel, moderately potent but lipophilic series. Optimization led to compounds 33 and 37, which exhibit potent inhibition of human ACC2, 10-fold selectivity over inhibition of human ACC1, good physical and in vitro ADME properties and good bioavailability. X-ray crystallography has shown this series binding in the CT-domain of ACC2 and revealed two key hydrogen bonding interactions. Both 33 and 37 lower levels of hepatic malonyl-CoA in vivo in obese Zucker rats. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：3039 / 3053

页数：15

共 38 条

[1] Mutant mice lacking acetyl-CoA carboxylase 1 are embryonically lethal [J].