Discovery of potent and liver-targeted stearoyl-CoA desaturase (SCD) inhibitors in a bispyrrolidine series

• Published in: Bioorganic & medicinal chemistry letters 2012-01, Vol.22 (2), p.980-984
• Main Authors: Lachance, Nicolas, Gareau, Yves, Guiral, Sébastien, Huang, Zheng, Isabel, Elise, Leclerc, Jean-Philippe, Léger, Serge, Martins, Evelyn, Nadeau, Christian, Oballa, Renata M., Ouellet, Stéphane G., Powell, David A., Ramtohul, Yeeman K., Tranmer, Geoffrey K., Trinh, Thao, Wang, Hao, Zhang, Lei
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; chemistry; Desaturation index; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; eyes; Hep G2 Cells; Humans; liver; Liver - drug effects; Liver - enzymology; Liver - metabolism; Liver-targeted; Medical sciences; mice; MK-8245; Molecular Structure; noninsulin-dependent diabetes mellitus; obesity; pharmacokinetics; Pharmacology. Drug treatments; Pyrrolidines - chemical synthesis; Pyrrolidines - chemistry; Pyrrolidines - pharmacology; Rats; SCD inhibitors; stearoyl-CoA desaturase; Stearoyl-CoA Desaturase - antagonists & inhibitors; Stearoyl-CoA Desaturase - metabolism; Stearoyl-CoA desaturase inhibitors; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.12.002

The synthesis of potent and liver-selective SCD inhibitors containing a bispyrrolidine as the tether joining the key heterocyclic core and terminal aromatic ring is described. Structure–activity relationships and in vivo biological activity of this new series of liver-targeting SCD inhibitors are reported. Inhibition of stearoyl-CoA desaturase (SCD) activity represents a potential novel mechanism for the treatment of metabolic disorders including obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed SCD inhibitors, our research efforts have been focused on the search for new and structurally diverse liver-targeted SCD inhibitors. This work has led to the discovery of novel, potent and structurally diverse liver-targeted bispyrrolidine SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.