Pharmacological characterization in vitro of EP2306 and EP2302, potent inhibitors of squalene synthase and lipid biosynthesis.
We investigated the effects of EP2306 and EP2302, two novel 2-biphenylmorpholine derivatives, on squalene synthase activity in rabbit and human liver microsomes, lipid biosynthesis, low-density lipoprotein (LDL) receptor expression and LDL protein uptake as well as apoB secretion in HepG2 cells. Both EP2306 and EP2302 inhibited squalene synthase activity dose-dependently. In rabbit liver microsomes, the IC50 values were 33 microM for EP2306 and 0.6 microM for EP2302 whereas in human liver microsomes, they were 63 microM for EP2306 and 1 microM for EP2302. Both EP2300 compounds inhibited cholesterol production by HepG2 cells dose dependently with IC50 values of 13.3 microM for EP2306 and 3 microM for EP2302. Furthermore, both EP2300 compounds and simvastatin significantly reduced triglyceride synthesis and apoB secretion and increased LDL receptor expression and LDL uptake in HepG2 cells. In summary, we have shown that EP2300 compounds are potent inhibitors of squalene synthase activity in rabbit and human liver microsomes and also they are effective inhibitors of cholesterol and triglyceride biosynthesis in HepG2 cells. These results suggest that EP2306 and EP2302 might prove to be useful for lipid-lowering and treatment of atherosclerosis in vivo.
ELPEN Pharmaceutical Co Inc., 95 Marathonos Av.,19009 Pikermi, Greece.
Anna
A
Tavridou
Loukas
L
Kaklamanis
George
G
Megaritis
Angeliki P
AP
Kourounakis
Apostolos
A
Papalois
Dimitris
D
Roukounas
Eleni A
EA
Rekka
Panos N
PN
Kourounakis
Avgui
A
Charalambous
Vangelis G
VG
Manolopoulos
D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008055:Lipids / Q000096:biosynthesis*; D008077:Lipoproteins, LDL / Q000493:pharmacokinetics; D008856:Microscopy, Fluorescence; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009025:Morpholines / Q000494:pharmacology*; D011817:Rabbits; D011973:Receptors, LDL / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology; D014280:Triglycerides / Q000096:biosynthesis
D001055:Apolipoproteins B; D001713:Biphenyl Compounds; C500325:EP2302; C500324:EP2306; D004791:Enzyme Inhibitors; D008055:Lipids; D008077:Lipoproteins, LDL; D009025:Morpholines; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol; D019821:Simvastatin; D013186:Farnesyl-Diphosphate Farnesyltransferase