Document Detail

Discovery of a Novel Acyl-CoA: Cholesterol Acyltransferase Inhibitor: The Synthesis, Biological Evaluation, and Reduced Adrenal Toxicity of (4-Phenylcoumarin)acetanilide Derivatives with a Carboxylic Acid Moiety.
MedLine Citation:
PMID:  22041073     Owner:  NLM     Status:  In-Data-Review    
As a part of our research for novel potent and orally available acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors that can be used as anti-atherosclerotic agents, we recently reported the discovery of the (4-phenylcoumarine)acetanilide derivative 1. However, compound 1 showed adrenal toxicity in animal models. In order to search for safer ACAT inhibitors that do not have adrenal toxicity, we examined the inhibitory activity of ACAT in human macrophage and adrenal cells. The introduction of a carboxylic acid moiety on the pendant phenyl ring and the adjustment of the lipophilicity led to the discovery of (2E)-3-[7-chloro-3-[2-[[4-fluoro-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl]-6-methyl-2-oxo-2H-chromen-4-yl]phenyl]acrylic acid (21e), which showed potent ACAT inhibitory activity in macrophages and a selectivity of around 30-fold over adrenal cells. In addition, compound 21e showed high adrenal safety in guinea pigs.
Masaki Ogino; Yoshihisa Nakada; Nobuyuki Negoro; Shigekazu Itokawa; Satoshi Nishimura; Tsukasa Sanada; Tomoko Satomi; Shunbun Kita; Kazuki Kubo; Shogo Marui
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Chemical & pharmaceutical bulletin     Volume:  59     ISSN:  1347-5223     ISO Abbreviation:  Chem. Pharm. Bull.     Publication Date:  2011  
Date Detail:
Created Date:  2011-11-01     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0377775     Medline TA:  Chem Pharm Bull (Tokyo)     Country:  Japan    
Other Details:
Languages:  eng     Pagination:  1369-75     Citation Subset:  IM    
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd.
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