University of Sussex
Browse

File(s) not publicly available

The squalestatins: inhibitors of squalene synthase. Enzyme inhibitory activities and in vivo evaluation of C-3 modified analogues

journal contribution
posted on 2023-06-08, 19:31 authored by Panayiotis A Procopiou, Brian Cox, Barrie E Kirk, Michael G Lester, Alun D McCarthy, Meenu Sareen, Peter J Sharratt, Michael A Snowden, Stephen J Spooner, Nigel S Watson, Julia Widdowson
Squalestatin analogues modified at C3 were prepared and evaluated for their ability to inhibit rat liver microsomal squalene synthase in vitro. While the 4,6-dimethyloctenoate ester group at C6 was maintained, a number of modifications to the C3 carboxylic acid were well tolerated. However, in the absence of the C6 ester group, similar modifications to the C3 carboxyl group caused loss of activity. Selected compounds were evaluated for their ability to inhibit cholesterol biosynthesis in vivo in rats 1 and 6 h postadministration. Analogues of squalestatin 1 (S1) modified at C3 were found to possess a shorter duration of effect in vivo which is reflected in their substantially reduced ability to lower serum cholesterol levels in marmosets. Significant cholesterol lowering (up to 62%) for the C3 hydroxymethyl analogue 1b was observed only when this compound was dosed three times a day for 3 days.

History

Publication status

  • Published

Journal

Journal of Medicinal Chemistry

ISSN

0022-2623

Publisher

American Chemical Society

Issue

7

Volume

39

Page range

1413-1422

Department affiliated with

  • Chemistry Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2015-01-13

Usage metrics

    University of Sussex (Publications)

    Categories

    No categories selected

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC