Although treatment with
statins significantly reduces adverse cardiovascular outcomes, several studies have shown that cardiovascular events continue to occur in two thirds of all patients. A logical pharmacologic approach to further reduce
cardiovascular disease mortality should be focused on direct modifiers of
atherosclerosis or
lipid-modifying agents with different mechanism of action than existing drugs against
dyslipidemia.
Squalene synthase inhibitors can decrease circulating
low-density lipoprotein (
LDL)-cholesterol by an increased expression of hepatic
LDL receptors in a similar manner to
statins. Also, depending on their structure, they may possess antiatherosclerotic properties independent of their
lipid-modifying effects. This review, following a brief introduction to different classes of
squalene synthase inhibitors and representative molecules, presents the accumulating in vitro and in vivo experimental evidence relevant to
squalene synthase inhibitors
EP2306 and
EP2302 and discusses their properties.
EP2306 and
EP2302 show a similar inhibitory effect in the progression of
atherosclerosis in the
cholesterol-fed rabbit. Moreover,
EP2306 showed a significant long-term antiatherosclerotic effect not shared by
simvastatin or their combination in this animal model.
EP2302 also showed a favorable effect in the regression of pre-established atherosclerotic lesions. It is reasonable to hypothesize that
EP2302, due to its NO-releasing and enhancing properties, could have additional advantages compared to
EP2306. Treatment with EP2300 compounds did not adversely affect liver
transaminases or cause toxicity on various organs of the
cholesterol-fed rabbit. The satisfactory safety profile of EP2300 compounds in this animal model is a promising finding in view of future clinical studies.