Inhibition of stearoyl-CoA desaturase by cyclic amine derivatives

Abstract

Stearoyl-CoA desaturase (SCD) is a central enzyme responsible for the synthesis of mono-unsaturated fatty acids, mainly oleate (C_18:1), a major component of tissue lipids. Recent studies have revealed that mice deficient in SCD1 have reduced tissue lipid accumulation and increased insulin sensitivity, and are resistant to diet- and leptin-deficiency-induced obesity. These facts demonstrate that SCD activity/gene expression inhibition may be a potential therapeutic target in the prevention of diabetes and the metabolic syndrome. This patent describes novel cyclic amine derivatives that inhibit SCD activity in liver and potentially may be used in combination with other drugs (e.g., PPARγ agonists, insulin or insulin mimetics, glucagon receptor antagonists, glucokinase activators). Based on their in vitro activity, it is probable that these compounds could be of therapeutic value for the treatment of disorders connected with obesity, but more experimental and clinical studies need to be done to validate these novel SCD inhibitors.

Keywords::

• atherosclerosis
• hepatic steatosis
• insulin resistance
• lipid disorders
• obesity