Pharmacologic inhibition of site 1 protease activity inhibits sterol regulatory element-binding protein processing and reduces lipogenic enzyme gene expression and lipid synthesis in cultured cells and experimental animals. The Journal of pharmacology and

Sterol regulatory element-binding proteins (SREBPs) are major transcriptional regulators of cholesterol, fatty acid, and glucose metabolism. Genetic disruption of SREBP activity reduces plasma and liver levels of cholesterol and triglycerides and insulin-stimulated lipogenesis, suggesting that SREBP is a vi-able target for pharmacological intervention. The proprotein convertase SREBP site 1 protease (S1P) is an important post-transcriptional regulator of SREBP activation. This report demonstrates that 10 M PF-429242 (Bioorg Med Chem Lett 17:4411–4414, 2007), a recently described reversible, compet-itive aminopyrrolidineamide inhibitor of S1P, inhibits endoge-nous SREBP processing in Chinese hamster ovary cells. The same compound also down-regulates the signal from an SRE-luciferase reporter gene in human embryonic kidney 293 cell