title: Discovery of triazolone derivatives as novel, potent stearoyl-CoA desaturase-1 (SCD1) inhibitors.
abstract: Stearoyl-CoA desaturase-1 (SCD1) plays an important role in lipid metabolism. Inhibition of SCD1 activity represents a potential novel approach for the treatment of metabolic diseases such as obesity, type 2 diabetes and dyslipidemia, as well as skin diseases, acne and cancer. Herein, we report the synthesis and structure-activity relationships (SAR) of a series of novel triazolone derivatives, culminating in the identification of pyrazolyltriazolone 17a, a potent SCD1 inhibitor, which reduced plasma C16:1/C16:0 triglycerides desaturation index (DI) in an acute Lewis rat model in a dose dependent manner, with an ED50 of 4.6 mg/kg. In preliminary safety studies, compound 17a did not demonstrate adverse effects related to SCD1 inhibition after repeat dosing at 100mg/kg. Together, these data suggest that sufficient safety margins can be achieved with certain SCD1 inhibitors, thus allowing exploration of clinical utility in metabolic disease settings.
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: Natalia
authors.initials: N
authors.lastname: Pokrovskaia
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: Qi
authors.initials: Q
authors.lastname: Jia
authors.affiliation: Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Elaine
authors.initials: E
authors.lastname: Chang
authors.affiliation: Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Kuldip
authors.initials: K
authors.lastname: Khakh
authors.affiliation: Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Rainbow
authors.initials: R
authors.lastname: Kwan
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 C
authors.initials: CC
authors.lastname: Radomski
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: Jianmin
authors.initials: J
authors.lastname: Fu
authors.affiliation: Novartis Institute for Biomedical Research, 250 Massachusetts Ave, Cambridge, MA 02139, USA. Electronic address: natalie.dales@novartis.com.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Dales
authors.affiliation: Xenon Pharmaceuticals Inc., 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Winther
mesh_terms: D000818:Animals; D055808:Drug Discovery; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008659:Metabolic Diseases / Q000188:drug therapy; D051379:Mice; D051381:Rats; D011917:Rats, Inbred Lew; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D014230:Triazoles; D013230:Stearoyl-CoA Desaturase
keywords: Desaturation index; Pyrazolyltriazolone; Stearoyl-CoA desaturase; Thiazolytriazolone