Indole inhibitors of human nonpancreatic secretory phospholipase A2. 1. Indole-3-acetamides.
Phospholipases (PLAs) produce rate-limiting precursors in the biosynthesis of various types of biologically active lipids involved in inflammatory processes. Increased levels of human nonpancreatic secretory phospholipase A2 (hnps-PLA2) have been detected in several pathological conditions. An inhibitor of this enzyme could have therapeutic utility. A broad screening program was carried out to identify chemical structures which could inhibit hnps-PLA2. One of the lead compounds generated by the screening program was 5-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid (13a). We describe the syntheses, structure--activity relationships, and pharmacological activities of a series of indole-3-acetamides and related compounds derived from this lead. This SAR was undertaken with the aid of X-ray crystal structures of complexes between the inhibitors and hnps-PLA2 which were of great value in directing the SAR.
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
D000818:Animals; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007210:Indoleacetic Acids / Q000737:chemistry / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007210:Indoleacetic Acids; C015950:indoleacetamide; D010741:Phospholipases A; D054467:Phospholipases A2