title: Biochemical characterization of cholesteryl ester transfer protein inhibitors.
abstract: 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.
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Mollie
authors.initials: M
authors.lastname: Ranalletta
authors.forename: Kathleen K
authors.initials: KK
authors.lastname: Bierilo
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Denise
authors.initials: D
authors.lastname: Milot
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.forename: Elaine
authors.initials: E
authors.lastname: Tung
authors.forename: Caroline
authors.initials: C
authors.lastname: Houde
authors.forename: Nadine H
authors.initials: NH
authors.lastname: Elowe
authors.forename: Margarita
authors.initials: M
authors.lastname: Garcia-Calvo
authors.forename: Gene
authors.initials: G
authors.lastname: Porter
authors.forename: Suzanne
authors.initials: S
authors.lastname: Eveland
authors.forename: Betsy
authors.initials: B
authors.lastname: Frantz-Wattley
authors.forename: Mike
authors.initials: M
authors.lastname: Kavana
authors.forename: George
authors.initials: G
authors.lastname: Addona
authors.forename: Peter
authors.initials: P
authors.lastname: Sinclair
authors.forename: Carl
authors.initials: C
authors.lastname: Sparrow
authors.forename: Edward A
authors.initials: EA
authors.lastname: O'Neill
authors.forename: Ken S
authors.initials: KS
authors.lastname: Koblan
authors.forename: Ayesha
authors.initials: A
authors.lastname: Sitlani
authors.forename: Brian
authors.initials: B
authors.lastname: Hubbard
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Fisher
mesh_terms: 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
chemical_list: 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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