Modulating cholesteryl ester transfer protein activity maintains efficient pre-β-HDL formation and increases reverse cholesterol transport.
The mechanism by which cholesteryl ester transfer protein (CETP) activity affects HDL metabolism was investigated using agents that selectively target CETP (dalcetrapib, torcetrapib, anacetrapib). In contrast with torcetrapib and anacetrapib, dalcetrapib requires cysteine 13 to decrease CETP activity, measured as transfer of cholesteryl ester (CE) from HDL to LDL, and does not affect transfer of CE from HDL3 to HDL2. Only dalcetrapib induced a conformational change in CETP, when added to human plasma in vitro, also observed in vivo and correlated with CETP activity. CETP-induced pre-β-HDL formation in vitro in human plasma was unchanged by dalcetrapib ≤3 µM and increased at 10 µM. A dose-dependent inhibition of pre-β-HDL formation by torcetrapib and anacetrapib (0.1 to 10 µM) suggested that dalcetrapib modulates CETP activity. In hamsters injected with [³H]cholesterol-labeled autologous macrophages, and given dalcetrapib (100 mg twice daily), torcetrapib [30 mg once daily (QD)], or anacetrapib (30 mg QD), only dalcetrapib significantly increased fecal elimination of both [³H]neutral sterols and [³H]bile acids, whereas all compounds increased plasma HDL-[³H]cholesterol. These data suggest that modulation of CETP activity by dalcetrapib does not inhibit CETP-induced pre-β-HDL formation, which may be required to increase reverse cholesterol transport.
Niesor
Eric J
EJ
Pharmaceuticals Division, F. Hoffmann-La Roche Ltd, Basel, Switzerland. eric_j.niesor@roche.com
Magg
Christine
C
Ogawa
Naoto
N
Okamoto
Hiroshi
H
von der Mark
Elisabeth
E
Matile
Hugues
H
Schmid
Georg
G
Clerc
Roger G
RG
Chaput
Evelyne
E
Blum-Kaelin
Denise
D
Huber
Walter
W
Thoma
Ralf
R
Pflieger
Philippe
P
Kakutani
Makoto
M
Takahashi
Daisuke
D
Dernick
Gregor
G
Maugeais
Cyrille
C
D000577:Amides; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000378:metabolism; D001665:Binding Sites; D001692:Biological Transport / Q000187:drug effects; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D053480:Cholesterol Ester Transfer Proteins / Q000097:blood / Q000378:metabolism*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D004952:Esters; D053442:High-Density Lipoproteins, Pre-beta / Q000097:blood / Q000378:metabolism*; D006801:Humans; D023303:Oxazolidinones / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000494:pharmacology
D000577:Amides; D000924:Anticholesteremic Agents; D001647:Bile Acids and Salts; D053480:Cholesterol Ester Transfer Proteins; D004952:Esters; D053442:High-Density Lipoproteins, Pre-beta; D023303:Oxazolidinones; D011804:Quinolines; D013438:Sulfhydryl Compounds; C411602:dalcetrapib; C483909:torcetrapib; D002784:Cholesterol; C530884:anacetrapib