Document Detail

Evacetrapib is a novel, potent, and selective inhibitor of cholesteryl ester transfer protein that elevates HDL cholesterol without inducing aldosterone or increasing blood pressure.
MedLine Citation:
PMID:  21957197     Owner:  NLM     Status:  MEDLINE    
Cholesteryl ester transfer protein (CETP) catalyses the exchange of cholesteryl ester and triglyceride between HDL and apoB containing lipoprotein particles. The role of CETP in modulating plasma HDL cholesterol levels in humans is well established and there have been significant efforts to develop CETP inhibitors to increase HDL cholesterol for the treatment of coronary artery disease. These efforts, however, have been hampered by the fact that most CETP inhibitors either have low potency or have undesirable side effects. In this study, we describe a novel benzazepine compound evacetrapib (LY2484595), which is a potent and selective inhibitor of CETP both in vitro and in vivo. Evacetrapib inhibited human recombinant CETP protein (5.5 nM IC(50)) and CETP activity in human plasma (36 nM IC(50)) in vitro. In double transgenic mice expressing human CETP and apoAI, evacetrapib exhibited an ex vivo CETP inhibition ED(50) of less than 5 mg/kg at 8 h post oral dose and significantly elevated HDL cholesterol. Importantly, no blood pressure elevation was observed in rats dosed with evacetrapib at high exposure multiples compared with the positive control, torcetrapib. In addition, in a human adrenal cortical carcinoma cell line (H295R cells), evacetrapib did not induce aldosterone or cortisol biosynthesis whereas torcetrapib dramatically induced aldosterone and cortisol biosynthesis. Our data indicate that evacetrapib is a potent and selective CETP inhibitor without torcetrapib-like off-target liabilities. Evacetrapib is currently in phase II clinical development.
Guoqing Cao; Thomas P Beyer; Youyan Zhang; Robert J Schmidt; Yan Q Chen; Sandra L Cockerham; Karen M Zimmerman; Sotirios K Karathanasis; Ellen A Cannady; Todd Fields; Nathan B Mantlo
Related Documents :
1170287 - Regulation of glucose-6 phosphate dehydrogenase and 6-phosphogluconate dehydrogenase in...
21691797 - In vitro gas production and dry matter degradability of diets consumed by goats with or...
12901467 - Does point-of-purchase nutrition labeling influence meal selections? a test in an army ...
3117097 - Effect of heat on the nutritional value of lupin (lupinus angustifolius)--seed meal for...
8558297 - Dietary soybean protein prevents bone loss in an ovariectomized rat model of osteoporosis.
7529157 - The ecotoxicological significance of cadmium intake and residues in terrestrial small m...
Publication Detail:
Type:  Journal Article     Date:  2011-09-25
Journal Detail:
Title:  Journal of lipid research     Volume:  52     ISSN:  0022-2275     ISO Abbreviation:  J. Lipid Res.     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-11-14     Completed Date:  2012-03-19     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  0376606     Medline TA:  J Lipid Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2169-76     Citation Subset:  IM    
Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, IN 46285, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Aldosterone / metabolism
Benzodiazepines / adverse effects*,  pharmacology*
Blood Pressure / drug effects
Cell Line, Tumor
Cholesterol Ester Transfer Proteins / antagonists & inhibitors*,  metabolism*
Cholesterol, HDL / blood*
Mice, Inbred NOD
Substrate Specificity
Reg. No./Substance:
0/Cholesterol Ester Transfer Proteins; 0/Cholesterol, HDL; 12794-10-4/Benzodiazepines; 51XWV9K850/evacetrapib; 52-39-1/Aldosterone

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Molecular characterization of seipin and its mutants: implications for seipin in triacylglycerol syn...
Next Document:  A biochemical fluorometric method for assessing the oxidative properties of HDL.