title: Discovery of piperazin-1-ylpyridazine-based potent and selective stearoyl-CoA desaturase-1 inhibitors for the treatment of obesity and metabolic syndrome.
abstract: Stearoyl-CoA desaturase-1 (SCD1) catalyzes de novo synthesis of monounsaturated fatty acids from saturated fatty acids. Studies have demonstrated that rodents lacking a functional SCD1 gene have an improved metabolic profile, including reduced weight gain, lower triglycerides, and improved insulin response. In this study, we discovered a series of piperazinylpyridazine-based highly potent, selective, and orally bioavailable compounds. Particularly, compound 49 (XEN103) was highly active in vitro (mSCD1 IC(50) = 14 nM and HepG2 IC(50) = 12 nM) and efficacious in vivo (ED(50) = 0.8 mg/kg). It also demonstrated striking reduction of weight gain in a rodent model. Our findings with small-molecule SCD1 inhibitors confirm the importance of this target in metabolic regulation, describe novel models for assessing SCD1 inhibitors for efficacy and tolerability and demonstrate an opportunity to develop a novel therapy for metabolic disease.
authors.affiliation: Xenon Pharmaceuticals, Inc., 3650 Gilmore Way, Burnaby, BC V5G 4W8 Canada.
authors.forename: Zaihui
authors.initials: Z
authors.lastname: Zhang
authors.forename: Shaoyi
authors.initials: S
authors.lastname: Sun
authors.forename: Vishnumurthy
authors.initials: V
authors.lastname: Kodumuru
authors.forename: Duanjie
authors.initials: D
authors.lastname: Hou
authors.forename: Shifeng
authors.initials: S
authors.lastname: Liu
authors.forename: Nagasree
authors.initials: N
authors.lastname: Chakka
authors.forename: Serguei
authors.initials: S
authors.lastname: Sviridov
authors.forename: Sultan
authors.initials: S
authors.lastname: Chowdhury
authors.forename: David G
authors.initials: DG
authors.lastname: McLaren
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Ratkay
authors.forename: Kuldip
authors.initials: K
authors.lastname: Khakh
authors.forename: Xing
authors.initials: X
authors.lastname: Cheng
authors.forename: Heinz W
authors.initials: HW
authors.lastname: Gschwend
authors.forename: Rajender
authors.initials: R
authors.lastname: Kamboj
authors.forename: Jianmin
authors.initials: J
authors.lastname: Fu
authors.forename: Michael D
authors.initials: MD
authors.lastname: Winther
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D024821:Metabolic Syndrome / Q000188:drug therapy*; D051379:Mice; D009765:Obesity / Q000188:drug therapy*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011924:Rats, Zucker; D021241:Spectrometry, Mass, Electrospray Ionization; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D010879:Piperazines; D011724:Pyridazines; D013230:Stearoyl-CoA Desaturase