title: Discovery of potent and liver-selective stearoyl-CoA desaturase (SCD) inhibitors in an acyclic linker series.
abstract: Elevated levels of stearoyl-CoA desaturase (SCD) activity have been implicated in metabolic disorders such as obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed inhibitors, our research efforts have been focused on the search for new liver-targeting compounds. This work has led to the discovery of novel, potent and liver-selective acyclic linker SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.
authors.affiliation: Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Hwy, Kirkland, Quebec, Canada H9H 3L1. nicolas.lachance21@gmail.com
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lachance
authors.forename: Sébastien
authors.initials: S
authors.lastname: Guiral
authors.forename: Zheng
authors.initials: Z
authors.lastname: Huang
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Leclerc
authors.forename: Chun Sing
authors.initials: CS
authors.lastname: Li
authors.forename: Renata M
authors.initials: RM
authors.lastname: Oballa
authors.forename: Yeeman K
authors.initials: YK
authors.lastname: Ramtohul
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Jin
authors.initials: J
authors.lastname: Wu
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008956:Models, Chemical; D009765:Obesity / Q000188:drug therapy; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: C561635:(5-(3-(4-(2-bromo-5-fluorophenoxy)piperidin-1-yl)isoxazol-5-yl)-2H-tetrazol-2-yl)acetic acid; D000085:Acetates; D004791:Enzyme Inhibitors; D013777:Tetrazoles; D013230:Stearoyl-CoA Desaturase