title: 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.
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.
authors.affiliation: AstraZeneca Research and Development, Mölndal, Sweden.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Bengtsson
authors.forename: Stefan
authors.initials: S
authors.lastname: Blaho
authors.forename: David Blomberg
authors.initials: DB
authors.lastname: Saitton
authors.forename: Kay
authors.initials: K
authors.lastname: Brickmann
authors.forename: Johan
authors.initials: J
authors.lastname: Broddefalk
authors.forename: Ojvind
authors.initials: O
authors.lastname: Davidsson
authors.forename: Tomas
authors.initials: T
authors.lastname: Drmota
authors.forename: Rutger
authors.initials: R
authors.lastname: Folmer
authors.forename: Kenth
authors.initials: K
authors.lastname: Hallberg
authors.forename: Stefan
authors.initials: S
authors.lastname: Hallén
authors.forename: Ragnar
authors.initials: R
authors.lastname: Hovland
authors.forename: Emre
authors.initials: E
authors.lastname: Isin
authors.forename: Petra
authors.initials: P
authors.lastname: Johannesson
authors.forename: Bengt
authors.initials: B
authors.lastname: Kull
authors.forename: Lars-Olof
authors.initials: LO
authors.lastname: Larsson
authors.forename: Lars
authors.initials: L
authors.lastname: Löfgren
authors.forename: Kristina E
authors.initials: KE
authors.lastname: Nilsson
authors.forename: Tobias
authors.initials: T
authors.lastname: Noeske
authors.forename: Nick
authors.initials: N
authors.lastname: Oakes
authors.forename: Alleyn T
authors.initials: AT
authors.lastname: Plowright
authors.forename: Volker
authors.initials: V
authors.lastname: Schnecke
authors.forename: Pernilla
authors.initials: P
authors.lastname: Ståhlberg
authors.forename: Pernilla
authors.initials: P
authors.lastname: Sörme
authors.forename: Hong
authors.initials: H
authors.lastname: Wan
authors.forename: Eric
authors.initials: E
authors.lastname: Wellner
authors.forename: Linda
authors.initials: L
authors.lastname: Oster
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009765:Obesity / Q000188:drug therapy* / Q000201:enzymology; D051381:Rats; D011924:Rats, Zucker; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D005227:Fatty Acids; D054852:Small Molecule Libraries; D008316:Malonyl Coenzyme A; D000103:Acetyl-CoA Carboxylase