Design, synthesis and structure–activity-relationship of 1,5-tetrahydronaphthyridines as CETP inhibitors

This Letter describes the discovery and SAR optimization of 1,5-tetrahydronaphthyridines, a new class of potent CETP inhibitors. The effort led to the identification of 21b and 21d with in vitro human plasma CETP inhibitory activity in the nanomolar range (IC50=23 and 22nM, respectively). Both 21b a...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2012-05, Vol.22 (9), p.3056-3062
Main Authors: Fernandez, Maria-Carmen, Escribano, Ana, Mateo, Ana I., Parthasarathy, Saravanan, Martin de la Nava, Eva M., Wang, Xiaodong, Cockerham, Sandra L., Beyer, Thomas P., Schmidt, Robert J., Cao, Guoqing, Zhang, Youyan, Jones, Timothy M., Borel, Anthony, Sweetana, Stephanie A., Cannady, Ellen A., Stephenson, Gregory, Frank, Scott, Mantlo, Nathan B.
Format: Article
Language:English
Subjects:
1,5-Tetrahydronaphthyridines
Animals
Biological and medical sciences
CETP inhibitor
chemistry
Cholesterol Ester Transfer Proteins - antagonists & inhibitors
Cholesterol, HDL
CVD
Dose-Response Relationship, Drug
Drug Design
General pharmacology
HDL-c
heterozygosity
Humans
Inhibitory Concentration 50
Medical sciences
Mice
Naphthyridines - chemical synthesis
Naphthyridines - pharmacology
Pharmacology. Drug treatments
Physicochemical properties. Structure-activity relationships
Structure-Activity Relationship
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Summary:This Letter describes the discovery and SAR optimization of 1,5-tetrahydronaphthyridines, a new class of potent CETP inhibitors. The effort led to the identification of 21b and 21d with in vitro human plasma CETP inhibitory activity in the nanomolar range (IC50=23 and 22nM, respectively). Both 21b and 21d exhibited robust HDL-c increase in hCETP/hApoA1 dual heterozygous mice model.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2012.03.075