The Squalestatins: Inhibitors of Squalene Synthase. Enzyme Inhibitory Activities and in Vivo Evaluation of C3-Modified Analogues

• DOI: 10.1021/jm950893j
• Publication Date: 2002-07-26T05:03:09Z
• Authors: Panayiotis A. Pro...; Brian Cox; Barrie E. Kirk; Michael G. Lester; Alun D. McCarthy; Meenu Sareen; Peter J. Sharratt; Michael A. Snowden; Stephen J. Spooner; Nigel S. Watson; Julia Widdowson
• Keywords: Squalene; Squalene monooxygenase; Side chain; Farnesyl-diphosphate farnesyltransferase

Squalestatin analogues modified in the C1 side chain were prepared and evaluated for their ability to inhibit rat liver microsomal Candida squalene synthase (SQS) vitro. While maintaining 4,6-dimethyloctenoate or 4,6-dimethyloctanoate ester groups at C6, a number of modifications well tolerated. However, absence C6 group, similar caused substantial loss activity. Compounds also cholesterol biosynthesis vivo rats reduce serum levels marmosets. These studies revealed that compounds with SQS inhibitory activities can possess different durations action lipid-lowering abilities.