Indole inhibitors of human nonpancreatic secretory phospholipase A2. 3. Indole-3-glyoxamides.
The preceding papers of this series detail the development of functionalized indole-3-acetamides as inhibitors of hnps-PLA2. We describe here the extension of the structure-activity relationship to include a series of indole-3-glyoxamide derivatives. Functionalized indole-3-glyoxamides with an acidic substituent appended to the 4- or 5-position of the indole ring were prepared and tested as inhibitors of hnps-PLA2. It was found that the indole-3-glyoxamides with a 4-oxyacetic acid substituent had optimal inhibitory activity. These inhibitors exhibited an improvement in potency over the best of the indole-3-acetamides, and LY315920 (6m) was selected for evaluation clinically as an hnps-PLA2 inhibitor.
Draheim
S E
SE
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
Bach
N J
NJ
Dillard
R D
RD
Berry
D R
DR
Carlson
D G
DG
Chirgadze
N Y
NY
Clawson
D K
DK
Hartley
L W
LW
Johnson
L M
LM
Jones
N D
ND
McKinney
E R
ER
Mihelich
E D
ED
Olkowski
J L
JL
Schevitz
R W
RW
Smith
A C
AC
Snyder
D W
DW
Sommers
C D
CD
Wery
J P
JP
D018360:Crystallography, X-Ray; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D013329:Structure-Activity Relationship; D013453:Sulfonylurea Compounds / Q000737:chemistry* / Q000494:pharmacology*
D013453:Sulfonylurea Compounds; C032160:glyoxamide; D010741:Phospholipases A; D054467:Phospholipases A2