Inhibition of vertebrate squalene epoxidase by extended and truncated analogues of trisnorsqualene alcohol.

The epoxidation of squalene to (3S)-2,3-epoxysqualene and subsequent cyclization to lanosterol are keys steps in vertebrate cholesterol biosynthesis. Trisnorsqualene alcohol (TNSA) has previously been reported as a potent inhibitor of vertebrate squalene epoxidase, with IC50 = 4 microM for pig liver (J. Am. Chem. Soc. 1989, 111, 1508-1510). Analogues with extended and truncated carbon skeletons have been prepared and tested for pig liver squalene epoxidase (SE) inhibition. Most of the structural analogues were poor inhibitors of vertebrate SE, with the exception of bisnorsqualene alcohol which had the same activity as TNSA. These results support the theory that an intact trisnorsqualene moiety is required for activity.