Amides of 4-hydroxy-8-methanesulfonylamino-quinoline-2-carboxylic acid as zinc-dependent inhibitors of Lp-PLA2

https://doi.org/10.1016/j.bmcl.2012.11.048Get rights and content

Abstract

AX10479, the phenyl amide of 4-hydroxy-8-methanesulfonylamino-quinoline-2-carboxylic acid, was identified as a Zn2+-dependent, 27 nM inhibitor of human plasma Lp-PLA2. 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.

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    Moreover, the IC50 value was reduced to 10 nM or less when the fluorine atom was substituted on the benzene ring. In addition, if a chiral carbon is bond with the amide moiety, bioactivity varies greatly according to different configuration [186]. Bis(5-amidino-2-benzimidazolyl) methane (BABIM, 128) is another Zn2+ dependent inhibitor whose target is trypsin, an enzyme of the serine protease family.

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These authors contributed equally to this work.

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