title: Discovery of potent, selective, orally bioavailable stearoyl-CoA desaturase 1 inhibitors.
abstract: Stearoyl-CoA desaturase 1 (SCD1) catalyzes the committed step in the biosynthesis of monounsaturated fatty acids from saturated, long-chain fatty acids. Studies with SCD1 knockout mice have established that these animals are lean and protected from leptin deficiency-induced and diet-induced obesity, with greater whole body insulin sensitivity than wild-type animals. In this work, we have discovered a series of potent, selective, orally bioavailable SCD1 inhibitors based on a known pyridazine carboxamide template. The representative lead inhibitor 28c also demonstrates excellent cellular activity in blocking the conversion of saturated long-chain fatty acid-CoAs (LCFA-CoAs) to monounsaturated LCFA-CoAs in HepG2 cells.
authors.affiliation: Metabolic Disease Research, Drug Metabolism, Advanced Technology, Exploratory Pharmacokinetics, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-6101, USA. liugx@gmail.com
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: John K
authors.initials: JK
authors.lastname: Lynch
authors.forename: Jennifer
authors.initials: J
authors.lastname: Freeman
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.forename: Zhili
authors.initials: Z
authors.lastname: Xin
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.forename: Michael D
authors.initials: MD
authors.lastname: Serby
authors.forename: Philip R
authors.initials: PR
authors.lastname: Kym
authors.forename: Tom S
authors.initials: TS
authors.lastname: Suhar
authors.forename: Harriet T
authors.initials: HT
authors.lastname: Smith
authors.forename: Ning
authors.initials: N
authors.lastname: Cao
authors.forename: Ruojing
authors.initials: R
authors.lastname: Yang
authors.forename: Rich S
authors.initials: RS
authors.lastname: Janis
authors.forename: Joel A
authors.initials: JA
authors.lastname: Krauser
authors.forename: Steven P
authors.initials: SP
authors.lastname: Cepa
authors.forename: David W A
authors.initials: DW
authors.lastname: Beno
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Christine A
authors.initials: CA
authors.lastname: Collins
authors.forename: Teresa K
authors.initials: TK
authors.lastname: Surowy
authors.forename: Heidi S
authors.initials: HS
authors.lastname: Camp
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D045744:Cell Line, Tumor; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000214:Acyl Coenzyme A; C531040:CAY10566; D010069:Oxadiazoles; D011724:Pyridazines; C523776:SCD1 protein, human; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase