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Design, Synthesis, and Biological Evaluation of 3-(1-Aryl-1H-indol-5-yl)propanoic Acids as New Indole-Based Cytosolic Phospholipase A2α Inhibitors

Design, Synthesis, and Biological Evaluation of 3-(1-Aryl-1H-indol-5-yl)propanoic Acids as New Indole-Based Cytosolic Phospholipase A2α Inhibitors

Toshiyuki Tomoo, Takashi Nakatsuka, Toyoko Katayama, Yasuhiro Hayashi, Yusuke Fujieda, Maki Terakawa, Kazuhiro Nagahira

J Med Chem. 2014 Sep 11;57(17):7244-62.

PMID: 25102418

Abstract:

This article 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1069046009	ASB14780		1069046-00-9	Price

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