Dibenzodioxocinones—A new class of CETP inhibitors

Dibenzodioxocinones with high inhibitory potential for CETP and good plasma stability were prepared by semisynthesis from a natural product precursor. Derivatives of the natural product 11-hydroxy-3-[( S)-1-hydroxy-3-methylbutyl]-4-methoxy-9-methyl-5 H,7 H-dibenzo[ b, g][1,5]dioxocin-5-one 1 were st...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2005-08, Vol.15 (15), p.3611-3614
Main Authors: Brückner, David, Hafner, Frank-Thorsten, Li, Volkhart, Schmeck, Carsten, Telser, Joachim, Vakalopoulos, Alexandros, Wirtz, Gabriele
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Carrier Proteins - antagonists & inhibitors
Carrier Proteins - blood
CETP
Cholesterol Ester Transfer Proteins
Dibenzodioxocinones
Dioxins - chemical synthesis
Dioxins - pharmacology
General and cellular metabolism. Vitamins
Glycoproteins - antagonists & inhibitors
Glycoproteins - blood
Heterocyclic Compounds, 3-Ring - chemical synthesis
Heterocyclic Compounds, 3-Ring - pharmacology
Hypolipidemic Agents - blood
Hypolipidemic Agents - chemical synthesis
Hypolipidemic Agents - pharmacology
Medical sciences
Pharmacology. Drug treatments
Rats
Structure-Activity Relationship
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Summary:Dibenzodioxocinones with high inhibitory potential for CETP and good plasma stability were prepared by semisynthesis from a natural product precursor. Derivatives of the natural product 11-hydroxy-3-[( S)-1-hydroxy-3-methylbutyl]-4-methoxy-9-methyl-5 H,7 H-dibenzo[ b, g][1,5]dioxocin-5-one 1 were studied as novel CETP inhibitors. Compound 2 was identified from HTS as a micromolar inhibitor. The compound suffered from very low stability in plasma. Optimisation by partial synthesis started from 1 and led to low-nanomolar inhibitors with good stability in rat plasma.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2005.05.073