Amides of 4-hydroxy-8-methanesulfonylamino-quinoline-2-carboxylic acid as zinc-dependent inhibitors of Lp-PLA

AX10479, the phenyl amide of 4-hydroxy-8-methanesulfonylamino-quinoline-2-carboxylic acid, was identified as a Zn(2+)-dependent, 27nM inhibitor of human plasma Lp-PLA(2). Structure-activity relationship studies focused on the AX10479 2-phenylamide group identified equipotent cycloaliphatic amides, a...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2013-03, Vol.23 (5), p.1553-1556
Hauptverfasser:	Hu, Yi, Lin, Emme C K, Pham, Lan M, Cajica, Julia, Amantea, Christopher M, Okerberg, Eric, Brown, Heidi E, Fraser, Allister, Du, Lingling, Kohno, Yasushi, Ishiyama, Junichi, Kozarich, John W, Shreder, Kevin R
Format:	Artikel
Sprache:	eng
Schlagworte:	1-Alkyl-2-acetylglycerophosphocholine Esterase - antagonists & inhibitors Amides - chemical synthesis Amides - chemistry Amides - pharmacology Humans Quinolines - chemical synthesis Quinolines - chemistry Quinolines - pharmacology Stereoisomerism Structure-Activity Relationship Zinc - chemistry
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Zusammenfassung:	AX10479, the phenyl amide of 4-hydroxy-8-methanesulfonylamino-quinoline-2-carboxylic acid, was identified as a Zn(2+)-dependent, 27nM inhibitor of human plasma Lp-PLA(2). Structure-activity relationship studies focused on the AX10479 2-phenylamide group identified equipotent cycloaliphatic amides, an enantioselective preference for chiral amides, and phenyl substitution patterns (e.g., 2-methyl-3-fluoro) that increased potency.
ISSN:	1464-3405
DOI:	10.1016/j.bmcl.2012.11.048