Amides of xanthurenic acid as zinc-dependent inhibitors of Lp-PLA(2).
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.
ActivX Biosciences, Inc., 11025 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Emme C K
EC
Lin
Yi
Y
Hu
Christopher M
CM
Amantea
Lan M
LM
Pham
Julia
J
Cajica
Eric
E
Okerberg
Heidi E
HE
Brown
Allister
A
Fraser
Lingling
L
Du
Yasushi
Y
Kohno
Junichi
J
Ishiyama
John W
JW
Kozarich
Kevin R
KR
Shreder
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000577:Amides / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014977:Xanthurenates / Q000737:chemistry*; D015032:Zinc / Q000737:chemistry*
D000577:Amides; D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; D014977:Xanthurenates; C028330:xanthurenic acid; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D015032:Zinc