Novel tetrahydrochinoline derived CETP inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 5, 2010, Pages 1740-1743

  Schmeck, Carsten ^a   Gielen Haertwig, Heike ^a   Vakalopoulos, Alexandros ^a   Bischoff, Hilmar ^a   Li, Volkhart ^a   Wirtz, Gabriele ^a   Weber, Olaf ^a  

^a BAYER PHARMA AG   (Germany)

Author keywords

CETP inhibitor; HDL; Tetrahydrochinolines; Torcetrapib

Indexed keywords

2 METHYLPROPANETHIOIC ACID S [2 [1 (2 ETHYLBUTYL)CYCLOHEXYLCARBOXAMIDO]PHENYL] ESTER; ANACETRAPIB; BAY 194789; BAY 381315; CHOLESTEROL ESTER TRANSFER PROTEIN INHIBITOR; DALCETRAPIB; QUINOLINE DERIVATIVE; TORCETRAPIB; UNCLASSIFIED DRUG;

ARTICLE; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; DRUG STRUCTURE; DRUG SYNTHESIS; ENANTIOSELECTIVITY; FLUORESCENCE ANALYSIS; IC 50; RISK REDUCTION; STRUCTURE ACTIVITY RELATION; TRANSGENIC MOUSE;

ANIMALS; ANTILIPEMIC AGENTS; CHOLESTEROL ESTER TRANSFER PROTEINS; DOGS; HUMANS; MICE; MICE, TRANSGENIC; QUINOLINES; RATS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; TETRAHYDRONAPHTHALENES;

MUS MUSCULUS;

EID: 76649087963     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.01.071     Document Type: Article

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20. 12, from Molecular Probes), 5.35 mg triolein (Sigma-Aldrich) and 6.67 mg POPC (Sigma-Aldrich), respectively, dissolved in a total volume of 600 μL dioxane and were slowly injected into 63 mL buffer (50 mM Tris/HCl pH 7.3, 150 mM NaCl, 2 mM EDTA) in a water bath sonicator. This suspension is then sonicated with 50 W (Branson Sonifier 450 with a cup-horn resonator) for 30 min under a nitrogen atmosphere at room temperature. (2) Acceptor liposomes were prepared in the same manner as donor liposomes using 86 mg cholesteryl-oleate, 20 mg triolein und 100 mg POPC dissolved in 1.2 mL dioxane and injected into 114 mL buffer. (3) In a total test volume of 100 μL test compounds dissolved in DMSO (2 μL) were incubated at 37 °C for 4 h with 50 μL of a CETP containing sample (1-3 μg CETP, enriched from human plasma) and 48 μL of a liposome emulsion (1 volume donor, 1 volume buffer and 2 volumes acceptor, respectively). The increase of the fluorescence intensity (excitation 485 nm, emission 535 nm) is proportional to the cholesterol ester transfer. The inhibition of the transfer is followed in comparison with a DMSO control.
21. To assess CETP activity in the presence of human plasma 6 μL (12% v/v) of donor liposomes and 1 μL (2% v/v) of a solution of the substance to be tested in DMSO are added to 42 μL (86% v/v) of human plasma (Sigma P 9523). The mixture is incubated at 37 °C for 24 h. The change in the fluorescence at 510/520 nm is a measure of the cholesterol ester transfer. The inhibition of the transfer is followed in comparison with a DMSO control.
22. 3 pH 7.4 containing 10 μL of CETP (1 mg/ml) and 3 μL of a solution of the substance to be tested (dissolved in 10% DMSO/1% BSA). 200 μL of the SPA-streptavidin bead solution (TRKQ 7005) are then added, incubated further with shaking for 1 h and then measured in a scintillation counter. Corresponding incubations with 10 μL of buffer, 10 μL of CETP serve as controls.
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