Discovery of spirocyclic-diamine inhibitors of mammalian acetyl CoA-carboxylase

• Published in: Bioorganic & medicinal chemistry letters 2015-11, Vol.25 (22), p.5352-5356
• Main Authors: Kung, Daniel W., Griffith, David A., Esler, William P., Vajdos, Felix F., Mathiowetz, Alan M., Doran, Shawn D., Amor, Paul A., Bagley, Scott W., Banks, Tereece, Cabral, Shawn, Ford, Kristen, Garcia-Irizarry, Carmen N., Landis, Margaret S., Loomis, Kathrine, McPherson, Kirk, Niosi, Mark, Rockwell, Kristin L., Rose, Colin, Smith, Aaron C., Southers, James A., Tapley, Susan, Tu, Meihua, Valentine, James J.
• Format: Article
• Language: English
• Subjects: ACC; Acetyl CoA-carboxylase; Acetyl Coenzyme A - metabolism; Acetyl-CoA Carboxylase - antagonists & inhibitors; Animals; Diamine; Drug Discovery; Enzyme Activation - drug effects; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Hepatocytes - drug effects; Hepatocytes - enzymology; Humans; Inhibitory Concentration 50; Models, Biological; Molecular Structure; Rats; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Spirocycle
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.09.035

[Display omitted] A novel series of spirocyclic-diamine based, isoform non-selective inhibitors of acetyl-CoA carboxylase (ACC) is described. These spirodiamine derivatives were discovered by design of a library to mimic the structural rigidity and hydrogen-bonding pattern observed in the co-crystal structure of spirochromanone inhibitor I. The lead compound 3.5.1 inhibited de novo lipogenesis in rat hepatocytes, with an IC50 of 0.30μM.