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Bioorg Med Chem. 2010 Jun 15;18(12):4238-48. doi: 10.1016/j.bmc.2010.04.096. Epub 2010 May 10.

Design, synthesis, and docking of highly hypolipidemic agents: Schizosaccharomyces pombe as a new model for evaluating alpha-asarone-based HMG-CoA reductase inhibitors.

Author information

1
Laboratorio de Toxicología Preclínica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional (IPN), Prol. Carpio y Plan de Ayala s/n, 11340 México, D.F., Mexico.

Abstract

A series of alpha-asarone-based analogues was designed by conducting docking experiments with published crystal structures of human HMG-CoA reductase. Indeed, synthesis and evaluation of this series showed a highly hypocholesterolemic in vivo activity in a murine model, as predicted by previous docking studies. In agreement with this model, the polar groups attached to the benzene ring could play a key role in the enzyme binding and probably also in its biological activity, mimicking the HMG-moiety of the natural substrate. The hypolipidemic action mechanism of these compounds was investigated by developing a simple, efficient, and novel model for determining HMG-CoA reductase inhibition. The partial purification of the enzyme from Schizosaccharomyces pombe allowed for testing of alpha-asarone- and fibrate-based analogues, resulting in positive and significant inhibitory activity.

PMID:
20576575
DOI:
10.1016/j.bmc.2010.04.096
[Indexed for MEDLINE]

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