Pharmacological Profile of SMP-797, a Novel Acyl-Coenzyme A: Cholesterol Acyltransferase Inhibitor with Inducible Effect on the Expression of Low-Density Lipoprotein Receptor

Abstract

We investigated the pharmacological profile of SMP-797, a novel hypocholesterolemic agent. SMP-797 showed inhibitory effects on acyl-coenzyme A: cholesterol acyltransferase (ACAT) activities in various microsomes and in human cell lines, and hypocholesterolemic effects in rabbits fed a cholesterol-rich diet and hamsters fed a normal diet. In hamsters, the reduction of total cholesterol level by SMP-797 was mainly due to the decrease of low-density lipoprotein (LDL) cholesterol level rather than that of very low-density lipoprotein (VLDL) cholesterol level. Interestingly, SMP-797 increased the hepatic low-density lipoprotein receptor expression in vivo when it decreased the low-density lipoprotein cholesterol level. SMP-797 also increased low-density lipoprotein receptor expression in HepG2 cells like atorvastatin, an HMG-CoA reductase inhibitor, although other acyl-coenzyme A: cholesterol acyltransferase inhibitor had no effect. In addition, SMP-797 had no effect on cholesterol synthesis in HepG2 cells. These results suggested that the increase of low-density lipoprotein receptor expression by SMP-797 was independent of its acyl-coenzyme A: cholesterol acyltransferase inhibitory action and did not result from the inhibition of hepatic cholesterol synthesis. In conclusion, these results suggest that SMP-797 is a novel hypocholesterolemic agent showing a cholesterol-lowering effect in which the increase of hepatic low-density lipoprotein receptor expression as well as the inhibition of acyl-coenzyme A: cholesterol acyltransferase is involved.

Synthesis and structure–activity relationships of N-(4-amino-2,6-diisopropylphenyl)-N’-(1,4-diarylpiperidine-4-yl)methylureas as anti-hyperlipidemic agents

“…1), with potent cholesterol-lowering activity and direct regressive effect on atherosclerotic lesions. 12 We have also shown that SMP-797, unlike other ACAT inhibitors, such as Avasimibe (CI-1011) and F12511, 12,13 up-regulates hepatic LDL-R expression. Furthermore, SMP-797 at a concentration much higher than that needed for LDL-R up-regulation had no effect on cholesterol synthesis in HepG2 cells.…”

The new acyl‐CoA cholesterol acyltransferase inhibitor SMP‐797 does not interact with statins via OATP1B1 in human cryopreserved hepatocytes and oocytes expressing systems

“…Co., Ltd. SMP-797 shows inhibitory effects on acyl coenzyme A: cholesterol acyltransferase (abbreviated as ACAT) activities and increases the hepatic low-density lipoprotein receptor (abbreviated as LDL-R) expression [1]. ACAT inhibitors reduce cholesteryl esters, macrophage content and atherosclerotic lesions in the aorta and femoral arteries in preclinical studies [2][3][4][5][6][7][8].…”