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

Bioorg Med Chem Lett. 2015 Nov 15;25(22):5352-6. doi: 10.1016/j.bmcl.2015.09.035. Epub 2015 Sep 15.

Abstract

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 0.30 μM.

Keywords: ACC; Acetyl CoA-carboxylase; Diamine; Spirocycle.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetyl Coenzyme A / metabolism*
  • Acetyl-CoA Carboxylase / antagonists & inhibitors*
  • Animals
  • 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*

Substances

  • Enzyme Inhibitors
  • Small Molecule Libraries
  • Spiro Compounds
  • Acetyl Coenzyme A
  • Acetyl-CoA Carboxylase