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  • BibTeX
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
Bioorganic & medicinal chemistry, 2011-05, Vol.19 (10), p.3039-3053
2011

Details

Autor(en) / Beteiligte
Titel
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
Ist Teil von
  • Bioorganic & medicinal chemistry, 2011-05, Vol.19 (10), p.3039-3053
Ort / Verlag
Amsterdam: Elsevier Ltd
Erscheinungsjahr
2011
Link zum Volltext
Quelle
Elsevier ScienceDirect Journals Complete
Beschreibungen/Notizen
  • 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.
Sprache
Englisch
Identifikatoren
ISSN: 0968-0896
eISSN: 1464-3391
DOI: 10.1016/j.bmc.2011.04.014
Titel-ID: cdi_proquest_miscellaneous_874184626
Format
–
Schlagworte
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

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