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

Yi Hu; Emme C K Lin; Lan M Pham; Julia Cajica; Christopher M Amantea; Eric Okerberg; Heidi E Brown; Allister Fraser; Lingling Du; Yasushi Kohno; Junichi Ishiyama; John W Kozarich; Kevin R Shreder

doi:10.1016/j.bmcl.2012.11.048

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

Bioorg Med Chem Lett. 2013 Mar 1;23(5):1553-6. doi: 10.1016/j.bmcl.2012.11.048. Epub 2012 Dec 8.

Authors

Yi Hu¹, Emme C K Lin, Lan M Pham, Julia Cajica, Christopher M Amantea, Eric Okerberg, Heidi E Brown, Allister Fraser, Lingling Du, Yasushi Kohno, Junichi Ishiyama, John W Kozarich, Kevin R Shreder

Affiliation

¹ ActivX Biosciences, Inc., 11025 N. Torrey Pines Road, La Jolla, CA 92037, USA.

PMID: 23333209
DOI: 10.1016/j.bmcl.2012.11.048

Abstract

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.

MeSH terms

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

Substances

Amides
Quinolines
quinoline-4-carboxylic acid
1-Alkyl-2-acetylglycerophosphocholine Esterase
Zinc