The squalestatins: decarboxy and 4-deoxy analogues as potent squalene synthase inhibitors.
Squalestatins without either the hydroxy group at C-4 or the carboxylic acid at C-3 or C-4 were prepared and evaluated for their ability to inhibit rat liver microsomal squalene synthase (SQS) in vitro. These modifications were well tolerated for compounds with the 4,6-dimethyloctenoate ester at C-6 (S1 series). However in analogues without the C-6 ester (H1 series), removal of the C-4 hydroxy group gave compounds with reduced potency, whereas decarboxylation at C-3 resulted in a dramatic loss of SQS inhibitory activity. In comparison with S1 1, C-4 deoxyS1 3 and C-3 decarboxyS1 10 have shorter in vivo durations of action on the inhibition of hepatic cholesterol biosynthesis in rats. C-4 deoxyS1 3 retains good serum cholesterol-lowering ability in marmosets, while C-3 decarboxyS1 10 showed only a marginal effect even at high dose.
Chan
C
C
Glaxo Wellcome Research & Development, Medicines Research Centre, Stevenage, Herfordshire, UK.
Andreotti
D
D
Cox
B
B
Dymock
B W
BW
Hutson
J L
JL
Keeling
S E
SE
McCarthy
A D
AD
Procopiou
P A
PA
Ross
B C
BC
Sareen
M
M
Scicinski
J J
JJ
Sharratt
P J
PJ
Snowden
M A
MA
Watson
N S
NS
D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002144:Callithrix; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats; D013185:Squalene / Q000378:metabolism; D013329:Structure-Activity Relationship; D014233:Tricarboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D000924:Anticholesteremic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D014233:Tricarboxylic Acids; C075117:squalestatin 1; D013185:Squalene; D002784:Cholesterol; D013186:Farnesyl-Diphosphate Farnesyltransferase