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://srodev.sussex.ac.uk/id/eprint/52101

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