Document Detail

Design, Synthesis, and Biological Evaluation of 3-(1-Aryl-1H-indol-5-yl)propanoic Acids as New Indole-based Cytosolic Phospholipase A2α Inhibitors.
MedLine Citation:
PMID:  25102418     Owner:  NLM     Status:  Publisher    
This paper describes the design, synthesis, and biological evaluation of new indole-based cytosolic phospholipase A2α (cPLA2α, a group IVA phospholipase A2) inhibitors. A screening-hit compound from our library, (E)-3-{4-[(4-chlorophenyl)thio]-3-nitrophenyl}acrylic acid (5), was used to design a class of 3-(1-aryl-1H-indol-5-yl)propanoic acids as new small molecule inhibitors. The resultant structure-activity relationships studied using the isolated enzyme and by cell-based assays revealed that the 1-(p-O-substituted)phenyl, 3-phenylethyl, and 5-propanoic acid groups on the indole core are essential for good inhibitory activity against cPLA2α. Optimization of the p-substituents on the N1 phenyl group led to the discovery of 56n (ASB14780), which was shown to be a potent inhibitor of cPLA2α via enzyme assay, cell-based assay, and guinea pig and human whole-blood assays. It displayed oral efficacy toward mice tetradecanoyl phorbol acetate-induced ear edema and guinea pig ovalbumin-induced asthma models.
Toshiyuki Tomoo; Takashi Nakatsuka; Toyoko Katayama; Yasuhiro Hayashi; Yusuke Fujieda; Maki Terakawa; Kazuhiro Nagahira
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-8-7
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  -     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2014 Aug 
Date Detail:
Created Date:  2014-8-7     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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