New low-density lipoprotein receptor upregulators acting via a novel mechanism.
The synthesis and biological activity of a new series of benzamides and related compounds that upregulate the expression of the low-density lipoprotein (LDL) receptor in human hepatocytes (HepG2 cells) by a novel mechanism are described. The lead compound, N-[5-[(3-cyclohexylpropionyl)amino]-2-methylphenyl]-4-hydroxybe nzamide (1, RPR102359), increased the expression of the LDL receptors in HepG2 cells by 80% when tested at a concentration of 3 microM. Mevinolin (lovastatin) was found to increase the LDL receptor expression by 70% at the same concentration. In contrast to mevinolin, 1 was found to have no effect on cholesterol biosynthesis in liver homogenates or in HepG2 cells at doses where substantial upregulation of the LDL receptor was observed and thus stimulated LDL receptor expression by a novel mechanism.
Ashton
M J
MJ
Rhône-Poulenc Rorer, Dagenham Research Centre, Essex, U.K.
Brown
T J
TJ
Fenton
G
G
Halley
F
F
Harper
M F
MF
Lockey
P M
PM
Porter
B
B
Roach
A G
AG
Stuttle
K A
KA
Vicker
N
N
Walsh
R J
RJ
D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular; D002460:Cell Line; D002784:Cholesterol / Q000096:biosynthesis; D006801:Humans; D007202:Indicators and Reagents; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008113:Liver Neoplasms; D008148:Lovastatin / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D010226:Parabens / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010655:Phenylenediamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011973:Receptors, LDL / Q000096:biosynthesis*; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
D001549:Benzamides; D007202:Indicators and Reagents; D010226:Parabens; D010655:Phenylenediamines; C100991:RPR 102359; D011973:Receptors, LDL; D002784:Cholesterol; D008148:Lovastatin