title: Systematic evaluation of amide bioisosteres leading to the discovery of novel and potent thiazolylimidazolidinone inhibitors of SCD1 for the treatment of metabolic diseases.
abstract: Several five- and six-membered heterocycles were introduced to replace the C2-position amide bond of the original 2-aminothiazole-based hit compound 5. Specifically, replacement of the amide bond with an imidazolidinone moiety yielded a novel and potent thiazolylimidazolidinone series of SCD1 inhibitors. XEN723 (compound 22) was identified after optimization of the thiazolylimidazolidinone series. This compound demonstrated a 560-fold improvement in in vitro potency and reduced plasma desaturation indices in a dose dependent manner, with an EC50 of 4.5 mg/kg.
authors.affiliation: Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada. Electronic address: ssun@xenon-pharma.com.
authors.forename: Shaoyi
authors.initials: S
authors.lastname: Sun
authors.affiliation: Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Zaihui
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Vishnumurthy
authors.initials: V
authors.lastname: Kodumuru
authors.affiliation: Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Natalia
authors.initials: N
authors.lastname: Pokrovskaia
authors.affiliation: Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Julia
authors.initials: J
authors.lastname: Fonarev
authors.affiliation: Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Qi
authors.initials: Q
authors.lastname: Jia
authors.affiliation: Novartis Institute for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Po-Yee
authors.initials: PY
authors.lastname: Leung
authors.affiliation: Novartis Institute for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tran
authors.affiliation: Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Ratkay
authors.affiliation: Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: David G
authors.initials: DG
authors.lastname: McLaren
authors.affiliation: Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Chris
authors.initials: C
authors.lastname: Radomski
authors.affiliation: Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Sultan
authors.initials: S
authors.lastname: Chowdhury
authors.affiliation: Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Fu
authors.affiliation: Novartis Institute for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Hubbard
authors.affiliation: Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Winther
authors.affiliation: Novartis Institute for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA. Electronic address: natalie.dales@novartis.com.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Dales
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D048289:Imidazolidines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D008659:Metabolic Diseases / Q000188:drug therapy / Q000201:enzymology; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D048289:Imidazolidines; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase
keywords: Amide bioisosteres; Desaturation index; SCD1 inhibitors; Stearoyl-CoA desaturase-1; Thiazolylimidazolidinone