title: Bicyclic heteroaryl inhibitors of stearoyl-CoA desaturase: from systemic to liver-targeting inhibitors.
abstract: Optimization of a lead thiazole amide MF-152 led to the identification of potent bicyclic heteroaryl SCD1 inhibitors with good mouse pharmacokinetic profiles. In a view to target the liver for efficacy and to avoid SCD1 inhibition in the skin and eyes where adverse effects were previously observed in rodents, representative systemically-distributed SCD1 inhibitors were converted into liver-targeting SCD1 inhibitors.
authors.affiliation: Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Hwy, Kirkland, Quebec, Canada H9H 3L1. ramtohul@hotmail.com
authors.forename: Yeeman K
authors.initials: YK
authors.lastname: Ramtohul
authors.forename: David
authors.initials: D
authors.lastname: Powell
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Leclerc
authors.forename: Serge
authors.initials: S
authors.lastname: Leger
authors.forename: Renata
authors.initials: R
authors.lastname: Oballa
authors.forename: Cameron
authors.initials: C
authors.lastname: Black
authors.forename: Elise
authors.initials: E
authors.lastname: Isabel
authors.forename: Chun Sing
authors.initials: CS
authors.lastname: Li
authors.forename: Sheldon
authors.initials: S
authors.lastname: Crane
authors.forename: Joel
authors.initials: J
authors.lastname: Robichaud
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Guay
authors.forename: Sébastien
authors.initials: S
authors.lastname: Guiral
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Huang
mesh_terms: D000577:Amides; D000818:Animals; D015195:Drug Design; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D008099:Liver / Q000187:drug effects; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; C544974:MF 152; D010879:Piperazines; D013844:Thiazoles; C523776:SCD1 protein, human; D013230:Stearoyl-CoA Desaturase