Biochemical characterization of cholesteryl ester transfer protein inhibitors.
Cholesteryl ester transfer protein (CETP) has been identified as a novel target for increasing HDL cholesterol levels. In this report, we describe the biochemical characterization of anacetrapib, a potent inhibitor of CETP. To better understand the mechanism by which anacetrapib inhibits CETP activity, its biochemical properties were compared with CETP inhibitors from distinct structural classes, including torcetrapib and dalcetrapib. Anacetrapib and torcetrapib inhibited CETP-mediated cholesteryl ester and triglyceride transfer with similar potencies, whereas dalcetrapib was a significantly less potent inhibitor. Inhibition of CETP by both anacetrapib and torcetrapib was not time dependent, whereas the potency of dalcetrapib significantly increased with extended preincubation. Anacetrapib, torcetrapib, and dalcetrapib compete with one another for binding CETP; however anacetrapib binds reversibly and dalcetrapib covalently to CETP. In addition, dalcetrapib was found to covalently label both human and mouse plasma proteins. Each CETP inhibitor induced tight binding of CETP to HDL, indicating that these inhibitors promote the formation of a complex between CETP and HDL, resulting in inhibition of CETP activity.
Ranalletta
Mollie
M
Merck Research Laboratories, Rahway, NJ 07065, USA.
Bierilo
Kathleen K
KK
Chen
Ying
Y
Milot
Denise
D
Chen
Qing
Q
Tung
Elaine
E
Houde
Caroline
C
Elowe
Nadine H
NH
Garcia-Calvo
Margarita
M
Porter
Gene
G
Eveland
Suzanne
S
Frantz-Wattley
Betsy
B
Kavana
Mike
M
Addona
George
G
Sinclair
Peter
P
Sparrow
Carl
C
O'Neill
Edward A
EA
Koblan
Ken S
KS
Sitlani
Ayesha
A
Hubbard
Brian
B
Fisher
Timothy S
TS
D000577:Amides; D000818:Animals; D000924:Anticholesteremic Agents / Q000737:chemistry* / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D004952:Esters; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D023303:Oxazolidinones / Q000737:chemistry* / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry* / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000737:chemistry* / Q000378:metabolism
D000577:Amides; D000924:Anticholesteremic Agents; D001798:Blood Proteins; D053480:Cholesterol Ester Transfer Proteins; D004952:Esters; D023303:Oxazolidinones; D011804:Quinolines; D013438:Sulfhydryl Compounds; C411602:dalcetrapib; C483909:torcetrapib; C530884:anacetrapib
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