| Evacetrapib is a novel, potent and selective inhibitor of cholesteryl ester transfer protein that elevates high-density lipoprotein cholesterol without inducing aldosterone or increasing blood pressure. | |
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MedLine Citation:
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PMID: 21957197 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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The role of Cholesteryl ester transfer protein (CETP) in modulating high-density lipoproteins (HDL) cholesterol levels in humans is well established and there have been significant efforts to develop CETP inhibitors 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 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 potently inhibited human recombinant CETP and activity in human plasma in vitro. In transgenic mice expressing human CETP and apolipoprotein AI, evacetrapib exhibited an ex vivo CETP inhibition ED50 of less than 5 mg/kg at 8 hours 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 to the positive control, torcetrapib. In addition, in a human adrenal cortical carcinoma cell line (H295R cells), evacetrapib did not induce aldosterone or cortisol biosynthesis compared to torcetrapib. 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. |
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Authors:
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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 |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-9-25 |
Journal Detail:
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Title: Journal of lipid research Volume: - ISSN: 0022-2275 ISO Abbreviation: - Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-9-29 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376606 Medline TA: J Lipid Res Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Lilly Research Laboratories, United States. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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