Abstract
A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea 15d, which demonstrated a reduction in cholesterol ester transfer activity (48% of predose level) in hCETP/apoB-100 dual transgenic mice. The PK profile of 15d was suboptimal, and further optimization of the N-terminus resulted in the discovery of amide 20 with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100 mice and in hamsters. Compound 20 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemeterized rats despite sustained high exposures.
MeSH terms
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Animals
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Anticholesteremic Agents / chemical synthesis
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Anticholesteremic Agents / chemistry*
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Anticholesteremic Agents / pharmacology*
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Apolipoprotein B-100 / antagonists & inhibitors
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Apolipoprotein B-100 / metabolism
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Blood Pressure / drug effects
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Cholesterol Ester Transfer Proteins / antagonists & inhibitors*
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Cholesterol Ester Transfer Proteins / metabolism
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Coronary Disease / drug therapy
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Cricetinae
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Drug Discovery
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Heart Rate / drug effects
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Humans
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Inhibitory Concentration 50
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Male
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Mice
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Mice, Transgenic
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Molecular Structure
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Pyridines / chemical synthesis
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Pyridines / chemistry*
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Pyridines / pharmacology*
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Rats
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Stilbenes / chemical synthesis
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Stilbenes / chemistry*
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Stilbenes / pharmacology*
Substances
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Anticholesteremic Agents
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Apolipoprotein B-100
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CETP protein, human
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Cholesterol Ester Transfer Proteins
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Pyridines
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Stilbenes