EP2300 compounds: focusing on the antiatherosclerotic properties of squalene synthase inhibitors.
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.
Tavridou
A
A
Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece. atavrid@med.duth.gr
Manolopoulos
V G
VG
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D050197:Atherosclerosis / Q000188:drug therapy* / Q000201:enzymology; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011817:Rabbits; D013329:Structure-Activity Relationship
D000975:Antioxidants; D001713:Biphenyl Compounds; C500325:EP2302; C500324:EP2306; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D009025:Morpholines; D013186:Farnesyl-Diphosphate Farnesyltransferase