title: N-benzylimidazole carboxamides as potent, orally active stearoylCoA desaturase-1 inhibitors.
abstract: A potent, small molecule inhibitor with a favorable pharmacokinetic profile to allow for sustained SCD inhibition in vivo was identified. Starting from a low MW acyl guanidine (5a), identified with a RapidFire High-Throughput Mass Spectrometry (RF-MS) assay, iterative library design was used to rapidly probe the amide and tail regions of the molecule. Singleton synthesis was used to probe core changes. Biological evaluation of a SCD inhibitor (5b) included in vitro potency at SCD-1 and in vivo modulation of the plasma desaturation index (DI) in rats on a low essential fatty acid (LEFA) diet. In addition to dose-dependent decrease in DI, effects on rodent ocular tissue were noted. Therefore, in rat, these SCD inhibitors only recapitulate a portion of phenotype exhibited by the SCD-1 knockout mouse.
authors.affiliation: Pfizer Global Research & Development, Groton Laboratories, Pfizer Inc., Groton, CT 06340, USA.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Atkinson
authors.forename: Elena E
authors.initials: EE
authors.lastname: Beretta
authors.forename: Janice A
authors.initials: JA
authors.lastname: Brown
authors.forename: Mayda
authors.initials: M
authors.lastname: Castrodad
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
authors.forename: Judith M
authors.initials: JM
authors.lastname: Cosgrove
authors.forename: Ping
authors.initials: P
authors.lastname: Du
authors.forename: John
authors.initials: J
authors.lastname: Litchfield
authors.forename: Michael
authors.initials: M
authors.lastname: Makowski
authors.forename: Kelly
authors.initials: K
authors.lastname: Martin
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: McLellan
authors.forename: Constantin
authors.initials: C
authors.lastname: Neagu
authors.forename: David A
authors.initials: DA
authors.lastname: Perry
authors.forename: David W
authors.initials: DW
authors.lastname: Piotrowski
authors.forename: Claire M
authors.initials: CM
authors.lastname: Steppan
authors.forename: Richard
authors.initials: R
authors.lastname: Trilles
mesh_terms: D000284:Administration, Oral; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D013058:Mass Spectrometry; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; C017062:1-benzylimidazole; D013230:Stearoyl-CoA Desaturase