Carbocyclic[g]indole inhibitors of human nonpancreatic s-PLA2.
A vinyl azide cyclization method was used to synthesize three different carbocyclic[g]indole scaffolds as inhibitors of human nonpancreatic secretory phospholipase A2. Each scaffold demonstrated potent enzyme activity in a chromogenic assay system, with select examples also demonstrating potent activity in a secondary DOC/PC assay. Compound 11, representative of the cyclopent[g]indole series, gave an IC50 of 10 nM for the inhibition of hnps-PLA2 in the chromogenic assay.
Sawyer
J Scott
JS
Discovery Chemistry Research and Technology, The Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. jss.dcrt@lilly.com
Beight
Douglas W
DW
Smith
Edward C R
EC
Snyder
David W
DW
Chastain
Marcia K
MK
Tielking
Richard L
RL
Hartley
Lawrence W
LW
Carlson
Donald G
DG
D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000737:chemistry; D054467:Phospholipases A2; D013329:Structure-Activity Relationship
C497154:2-((3-(2-amino-1,2-dioxoethyl)-2-methyl-1-benzyl-1,6,7,8-tetrahydrocyclopent(g)indol-4-yl)oxy)acetic acid; D000085:Acetates; D003517:Cyclopentanes; D007211:Indoles; D010741:Phospholipases A; D054467:Phospholipases A2