Amides of xanthurenic acid as zinc-dependent inhibitors of Lp-PLA(2)

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

doi:10.1016/j.bmcl.2011.12.045

Amides of xanthurenic acid as zinc-dependent inhibitors of Lp-PLA(2)

Bioorg Med Chem Lett. 2012 Jan 15;22(2):868-71. doi: 10.1016/j.bmcl.2011.12.045. Epub 2011 Dec 13.

Authors

Emme C K Lin¹, Yi Hu, Christopher M Amantea, Lan M Pham, Julia Cajica, 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: 22217870
DOI: 10.1016/j.bmcl.2011.12.045

Abstract

AX10185, the phenyl amide of xanthurenic acid, was found to be a sub-100nM inhibitor of Lp-PLA(2). However, in the presence of EDTA the inhibitory activity of AX10185 was extinguished while the enzymatic activity of Lp-PLA(2) did not change. Subsequent metal screening experiments determined the inhibition to be Zn(2+) dependent. Structure-activity relationship studies indicated the presence of the 4-hydroxy group to be critical and selected substituted phenyl, polycyclic, and cycloaliphatic amides of xanthurenic acid to be well tolerated.

MeSH terms

1-Alkyl-2-acetylglycerophosphocholine Esterase / antagonists & inhibitors*
1-Alkyl-2-acetylglycerophosphocholine Esterase / metabolism
Amides / chemistry*
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Molecular Structure
Organometallic Compounds / chemical synthesis
Organometallic Compounds / chemistry
Organometallic Compounds / pharmacology*
Structure-Activity Relationship
Xanthurenates / chemistry*
Zinc / chemistry*

Substances

Amides
Enzyme Inhibitors
Organometallic Compounds
Xanthurenates
xanthurenic acid
1-Alkyl-2-acetylglycerophosphocholine Esterase
Zinc