title: Identification and synthesis of novel inhibitors of acetyl-CoA carboxylase with in vitro and in vivo efficacy on fat oxidation.
abstract: Acetyl CoA carboxylase isoforms 1 and 2 (ACC1/2) are key enzymes of fat utilization and their inhibition is considered to improve aspects of the metabolic syndrome. To identify pharmacological inhibitors of ACC1/2, a high throughput screen was performed which resulted in the identification of the lead compound 3 ( Gargazanli , G. ; Lardenois , P. ; Frost , J. ; George , P. Patent WO9855474 A1, 1998 ) as a moderate selective ACC2 inhibitor. Optimization of 3 led to 4m ( Zoller , G. ; Schmoll , D. ; Mueller , M. ; Haschke , G. ; Focken , I. Patent WO2010003624 A2, 2010 ) as a submicromolar dual ACC1/2 inhibitor of the rat and human isoforms. 4m possessed favorable pharmacokinetic parameters. This compound stimulated fat oxidation in vivo and reduced plasma triglyceride levels in a rodent model after subchronic administration. 4m is a suitable tool compound for the elucidation of the pharmacological potential of ACC1/2 inhibition.
authors.affiliation: Sanofi-Aventis Deutschland GmbH, R&D, Diabetes Division, Industriepark Hoechst, Building G 878, D-65926 Frankfurt am Main, Germany. stefanie.keil@sanofi-aventis.com
authors.forename: Stefanie
authors.initials: S
authors.lastname: Keil
authors.forename: Marco
authors.initials: M
authors.lastname: Müller
authors.forename: Gerhard
authors.initials: G
authors.lastname: Zoller
authors.forename: Guido
authors.initials: G
authors.lastname: Haschke
authors.forename: Katrin
authors.initials: K
authors.lastname: Schroeter
authors.forename: Maike
authors.initials: M
authors.lastname: Glien
authors.forename: Sven
authors.initials: S
authors.lastname: Ruf
authors.forename: Ingo
authors.initials: I
authors.lastname: Focken
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Herling
authors.forename: Dieter
authors.initials: D
authors.lastname: Schmoll
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors*; D000818:Animals; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D051379:Mice; D008820:Mice, Obese; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000097:blood
chemical_list: D000081:Acetamides; D007527:Isoenzymes; C555226:N-(3-(4-(6-isopropoxypyridin-3-yloxy)phenyl)-1-methylpropyl)acetamide; D011725:Pyridines; D014280:Triglycerides; D019308:Palmitic Acid; D000103:Acetyl-CoA Carboxylase