Indole inhibitors of human nonpancreatic secretory phospholipase A2. 2. Indole-3-acetamides with additional functionality.
As reported in our previous paper, a series of indole-3-acetamides which possessed potency and selectivity as inhibitors of human nonpancreatic secretory phospholipase A2(hnps-PLA2) was developed. The design of these compounds was based on information derived from x-ray crystal structures determined for complexes between the enzyme and its inhibitors. We describe here the further implementation of this structure-based design strategy and continued SAR development to produce indole-3-acetamides with additional functionalities which provide increased interaction with important residues within the enzyme active site. These efforts led to inhibitors with substantially enhanced potency and selectivity.
Dillard
R D
RD
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
Bach
N J
NJ
Draheim
S E
SE
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; D007210:Indoleacetic Acids / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D013329:Structure-Activity Relationship
D007210:Indoleacetic Acids; C015950:indoleacetamide; D010741:Phospholipases A; D054467:Phospholipases A2