Squalestatin 1, a potent inhibitor of squalene synthase, which lowers serum cholesterol in vivo.
Squalestatin 1 is a member of a novel family of fermentation products isolated from a previously unknown Phoma species (Coelomycetes). Squalestatin 1 is a potent, selective inhibitor of squalene synthase, a key enzyme in cholesterol biosynthesis; in vitro, 50% inhibition of enzyme activity is observed at a concentration of 12 +/- 5 nM (range of 4-22 nM). Squalestatin 1 inhibits cholesterol biosynthesis from [14C]acetate by isolated rat hepatocytes (50% inhibition at 39 nM) and by rat liver in vivo. In marmosets, a species with a lipoprotein profile similar to that of man, squalestatin 1 lowers serum cholesterol by up to 75%. This compound will allow further investigation of the control of the sterol biosynthesis pathway and could also lead to the development of new therapies for elevated serum cholesterol.
Baxter
A
A
Glaxo Group Research Ltd., Greenford, Middlesex, United Kingdom.
Fitzgerald
B J
BJ
Hutson
J L
JL
McCarthy
A D
AD
Motteram
J M
JM
Ross
B C
BC
Sapra
M
M
Snowden
M A
MA
Watson
N S
NS
Williams
R J
RJ
D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D001055:Apolipoproteins B / Q000097:blood; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002144:Callithrix; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D051381:Rats; D014233:Tricarboxylic Acids / Q000494:pharmacology*
D016632:Apolipoprotein A-I; D001055:Apolipoproteins B; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D014233:Tricarboxylic Acids; C075117:squalestatin 1; D002784:Cholesterol; D013186:Farnesyl-Diphosphate Farnesyltransferase