title: Benzimidazole-carboxamides as potent and bioavailable stearoyl-CoA desaturase (SCD1) inhibitors from ligand-based virtual screening and chemical optimization.
abstract: The discovery of potent benzimidazole stearoyl-CoA desaturase (SCD1) inhibitors by ligand-based virtual screening is described. ROCS 3D-searching gave a favorable chemical motif that was subsequently optimized to arrive at a chemical series of potent and promising SCD1 inhibitors. In particular, compound SAR224 was selected for further pharmacological profiling based on favorable in vitro data. After oral administration to male ZDF rats, this compound significantly decreased the serum fatty acid desaturation index, thus providing conclusive evidence for SCD1 inhibition in vivo by SAR224.
authors: Sanofi-Aventis Deutschland GmbH, Research and Development, D-65926 Frankfurt am Main, Germany. Hans.Matter@sanofi.com
authors: Hans
authors: H
authors: Matter
authors: Gerhard
authors: G
authors: Zoller
authors: Andreas W
authors: AW
authors: Herling
authors: Juan-Antonio
authors: JA
authors: Sanchez-Arias
authors: Christophe
authors: C
authors: Philippo
authors: Claudie
authors: C
authors: Namane
authors: Markus
authors: M
authors: Kohlmann
authors: Anja
authors: A
authors: Pfenninger
authors: Marc D
authors: MD
authors: Voss
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry*; D001682:Biological Availability; D018938:Caco-2 Cells; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D011485:Protein Binding; D051381:Rats; D011924:Rats, Zucker; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D000577:Amides; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D008024:Ligands; C583200:SAR224; D013876:Thiophenes; C031000:benzimidazole; D013230:Stearoyl-CoA Desaturase