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The squalestatins: decarboxy and 4-deoxy analogues as potent squalene synthase inhibitors.

Abstract：

: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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Chan C,Andreotti D,Cox B,Dymock BW,Hutson JL,Keeling SE,McCarthy AD,Procopiou PA,Ross BC,Sareen M,Scicinski JJ,Sharratt PJ,Snowden MA,Watson NS

doi

10.1021/jm9504969

subject

Has Abstract

pub_date

1996-01-05 00:00:00

pages

207-16

issue

1

eissn

0022-2623

issn

1520-4804

pii

jm9504969

journal_volume

39

pub_type

杂志文章

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