RPR 102359 upregulates LDL-receptors in a cultured human hepatocyte cell line by a sterol-independent mechanism

Brown, Thomas J.; White, Ann L.; Lloyd, Jennifer; Wong, Megan; Vicker, Nigel; Lockey, Peter

doi:10.1016/0021-9150(94)93467-3

Cited by 2 publications

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“…A new series of compounds possessing potent in vitro activity for upregulating LDL receptors of HepG2 cells has been discovered, and three new series related to compound 1 with good activities (exemplified by compounds 20, 27, and 35 ) have been identified. Further testing confirmed that compound 1 does not inhibit cholesterol biosynthesis: neither by direct enzyme inhibition of cholesterol biosynthesis nor by attenuating HMG CoA reductase gene transcription . Figure shows that compound 1 is able to produce an additional degree of upregulation of receptors, in the presence of a maximally upregulating concentration of mevinolin, again suggesting that its mechanism of action is not through inhibition of sterol formation.…”

Section: Discussionmentioning

confidence: 86%

“…Further testing confirmed that compound 1 does not inhibit cholesterol biosynthesis: neither by direct enzyme inhibition of cholesterol biosynthesis nor by attenuating HMG CoA reductase gene transcription. 14 shows that compound 1 is able to produce an additional degree of upregulation of receptors, in the presence of a maximally upregulating concentration of mevinolin, again suggesting that its mechanism of action is not through inhibition of sterol formation. Compound 1 was also shown not to stimulate or inhibit ACAT activity in HepG2 cells.…”

Section: -2) Conclusionmentioning

confidence: 95%

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New Low-Density Lipoprotein Receptor Upregulators Acting via a Novel Mechanism

Ashton¹,

Brown²,

Fenton³

et al. 1996

J. Med. Chem.

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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.

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Section: Discussionmentioning

confidence: 86%

Section: -2) Conclusionmentioning

confidence: 95%