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

Chan, Chuen, Andreotti, Daniele, Cox, Brian, Dymock, Brian W, Hutson, Julie L, Keeling, Suzanne E, McCarthy, Alun D, Procopiou, Panayiotis A, Ross, Barry C, Sareen, Meenu, Scicinski, Jan J, Sharratt, Peter J, Snowden, Michael A and Watson, Nigel S (1996) The squalestatins: decarboxy and 4-deoxy analogues as potent squalene synthase inhibitors. Journal of Medicinal Chemistry, 39 (1). pp. 207-216. ISSN 0022-2623

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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.

Item Type: Article
Schools and Departments: School of Life Sciences > Chemistry
Subjects: Q Science > QD Chemistry
Depositing User: Tom Gittoes
Date Deposited: 13 Jan 2015 15:31
Last Modified: 13 Jan 2015 15:31
URI: http://sro.sussex.ac.uk/id/eprint/52101
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