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

journal contribution
posted on 2023-06-08, 19:31 authored by Chuen Chan, Daniele Andreotti, Brian Cox, Brian W Dymock, Julie L Hutson, Suzanne E Keeling, Alun D McCarthy, Panayiotis A Procopiou, Barry C Ross, Meenu Sareen, Jan J Scicinski, Peter J Sharratt, Michael A Snowden, Nigel S Watson
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.

History

Publication status

  • Published

Journal

Journal of Medicinal Chemistry

ISSN

0022-2623

Publisher

American Chemical Society

Issue

1

Volume

39

Page range

207-216

Department affiliated with

  • Chemistry Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2015-01-13

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