The squalestatins: novel inhibitors of squalene synthase. Enzyme inhibitory activities and in vivo evaluation of C1-modified analogues.
Squalestatin analogues modified in the C1 side chain were prepared and evaluated for their ability to inhibit rat liver microsomal and Candida squalene synthase (SQS) in vitro. While maintaining the 4,6-dimethyloctenoate or 4,6-dimethyloctanoate ester groups at C6, a number of modifications to the C1 side chain were well tolerated. However, in the absence of the C6 ester group, similar modifications to the C1 side chain caused substantial loss of activity. Compounds were also evaluated for their ability to inhibit cholesterol biosynthesis in vivo in rats and to reduce serum cholesterol levels in marmosets. These studies revealed that compounds with similar SQS inhibitory activities can possess different in vivo durations of action and lipid-lowering abilities.
Procopiou
P A
PA
Glaxo Research and Development Ltd., Greenford, Middlesex, United Kingdom.
Bailey
E J
EJ
Bamford
M J
MJ
Craven
A P
AP
Dymock
B W
BW
Houston
J G
JG
Hutson
J L
JL
Kirk
B E
BE
McCarthy
A D
AD
Sareen
M
M
D000818:Animals; D000924:Anticholesteremic Agents / Q000737:chemistry / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000737:chemistry* / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002144:Callithrix; D002176:Candida albicans / Q000201:enzymology; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D005260:Female; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000201:enzymology; D008862:Microsomes, Liver / Q000201:enzymology; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship; D014233:Tricarboxylic Acids / Q000737:chemistry* / Q000494:pharmacology
D000924:Anticholesteremic Agents; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D014233:Tricarboxylic Acids; C075117:squalestatin 1; D002784:Cholesterol; D013186:Farnesyl-Diphosphate Farnesyltransferase