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.
Bioorg Med Chem
; 19(10): 3039-53, 2011 May 15.
Article
in En
| MEDLINE
| ID: mdl-21515056
ABSTRACT
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.
Full text:
1
Database:
MEDLINE
Main subject:
Acetyl-CoA Carboxylase
/
Diabetes Mellitus, Type 2
/
Enzyme Inhibitors
/
Small Molecule Libraries
/
Obesity
Limits:
Animals
/
Humans
/
Male
Language:
En
Year:
2011
Type:
Article