title: Discovery of thiazolylpyridinone SCD1 inhibitors with preferential liver distribution and reduced mechanism-based adverse effects.
abstract: We discovered a series of novel and potent thiazolylpyridinone-based SCD1 inhibitors based on a 2-aminothiazole HTS hit by replacing the amide bond with a pyridinone moiety. Compound 19 demonstrated good potency against SCD1 in vitro and in vivo. The mouse liver microsomal SCD1 in vitro potency for 19 was improved by more than 240-fold compared to the original HTS hit. Furthermore, 19 demonstrated a dose-dependent reduction of plasma desaturation index with an ED50 of 6.3 mg/kg. Compound 19 demonstrated high liver to plasma and liver to eyelid exposures, indicating preferential liver distribution. The preliminary toxicology study with compound 19 did not demonstrate adverse effects related to SCD1 inhibition, suggesting a wide safety margin with respect to other known SCD1 inhibitors with wider distribution profiles.
authors.affiliation: Xenon Pharmaceuticals Inc., 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., 3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Zaihui
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Xenon Pharmaceuticals Inc., 3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Vandna
authors.initials: V
authors.lastname: Raina
authors.affiliation: Xenon Pharmaceuticals Inc., 3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Natalia
authors.initials: N
authors.lastname: Pokrovskaia
authors.affiliation: Xenon Pharmaceuticals Inc., 3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Duanjie
authors.initials: D
authors.lastname: Hou
authors.affiliation: Xenon Pharmaceuticals Inc., 3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Rostam
authors.initials: R
authors.lastname: Namdari
authors.affiliation: Xenon Pharmaceuticals Inc., 3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Kuldip
authors.initials: K
authors.lastname: Khakh
authors.affiliation: Xenon Pharmaceuticals Inc., 3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Ratkay
authors.affiliation: Xenon Pharmaceuticals Inc., 3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: David G
authors.initials: DG
authors.lastname: McLaren
authors.affiliation: Xenon Pharmaceuticals Inc., 3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Monica
authors.initials: M
authors.lastname: Mork
authors.affiliation: Xenon Pharmaceuticals Inc., 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: Suzie
authors.initials: S
authors.lastname: Ferreira
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., 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
authors.initials: N
authors.lastname: Dales
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D011728:Pyridones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
chemical_list: D011728:Pyridones; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase
keywords: Desaturation index; Liver selective; SCD1 inhibitors; Stearoyl-CoA desaturase-1; Thiazolylpyridinone