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

• Published in: Bioorganic & medicinal chemistry 2011-05, Vol.19 (10), p.3039-3053
• Main Authors: Bengtsson, Christoffer, Blaho, Stefan, Saitton, David Blomberg, Brickmann, Kay, Broddefalk, Johan, Davidsson, Öjvind, Drmota, Tomas, Folmer, Rutger, Hallberg, Kenth, Hallén, Stefan, Hovland, Ragnar, Isin, Emre, Johannesson, Petra, Kull, Bengt, Larsson, Lars-Olof, Löfgren, Lars, Nilsson, Kristina E., Noeske, Tobias, Oakes, Nick, Plowright, Alleyn T., Schnecke, Volker, Ståhlberg, Pernilla, Sörme, Pernilla, Wan, Hong, Wellner, Eric, Öster, Linda
• Format: Article
• Language: English
• Subjects: Acetyl-CoA carboxylase; Acetyl-CoA Carboxylase - antagonists & inhibitors; Acetyl-CoA Carboxylase - metabolism; Animals; beta oxidation; bioavailability; Biological and medical sciences; biosynthesis; Crystallography, X-Ray; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - enzymology; Drug Design; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; fatty acids; Fatty Acids - metabolism; General and cellular metabolism. Vitamins; Humans; hybridization; hydrogen bonding; Ligand lipophilicity efficiency; Liver - drug effects; Liver - enzymology; Male; Malonyl Coenzyme A - metabolism; Malonyl-CoA; Medical sciences; Mice; Mice, Inbred C57BL; Models, Molecular; Obesity - drug therapy; Obesity - enzymology; Pharmacology. Drug treatments; Quinoline; Rats; Rats, Zucker; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacokinetics; Small Molecule Libraries - pharmacology; Small Molecule Libraries - therapeutic use; Structure-Activity Relationship; X-ray diffraction
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.04.014

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.