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

详细信息    查看全文

• 作者：Christoffer Bengtsson^a ; Stefan Blaho^a ; David Blomberg Saitton^a ; Kay Brickmann^a ; Johan Broddefalk^a ; Ö ; jvind Davidsson^a ; Tomas Drmota^a ; Rutger Folmer^a ; Kenth Hallberg^a ; Stefan Hallé ; n^a ; Ragnar Hovland^a ; Emre Isin^a ; Petra Johannesson^a ; Bengt Kull^a ; Lars-Olof Larsson^a ; Lars L&#xf6 ; fgren^a ; Kristina E. Nilsson^a ; Tobias Noeske^a ; Nick Oakes^a ; Alleyn T. Plowright ; ^a ; ^{alleyn.plowright@astrazeneca.com"" rel=""nofollow} ; Volker Schnecke^a ; Pernilla Stå ; hlberg^a ; Pernilla S&#xf6 ; rme^a ; Hong Wan^a ; Eric Wellner^a ; Linda Ö ; ster^a
• 关键词：Acetyl-CoA carboxylase ; Malonyl-CoA ; Ligand lipophilicity efficiency ; Quinoline
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2011
• 出版时间：15 May 2011
• 年：2011
• 卷：19
• 期：10
• 页码：3039-3053
• 全文大小：2006 K

文摘

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.