Structure‐Activity Relationship Studies of 1‐Substituted 3‐Dodecanoylindole‐2‐carboxylic Acids as Inhibitors of Cytosolic Phospholipase A₂‐Mediated Arachidonic Acid Release in Intact Platelets

Abstract

A series of 3-dodecanoylindole-2-carboxylic acid derivatives with varied carboxylic acid substituents at the indole 1-position were synthesized and evaluated for their ability to inhibit arachidonic acid release in human platelets mediated by the cytosolic phospholipase A(2). Structure-activity relationship studies revealed that increasing the polarity of these substituents by the introduction of additional polar groups in the proximity of the carboxylic acid moiety reduced activity. Conformational restriction of the indole-1-carboxylic acid substituents in distinct positions as well as extending the length of these residues led to compounds which did not substantially differ in their potencies.

Structure–activity relationship studies of 3-dodecanoylindole-2-carboxylic acid inhibitors of cytosolic phospholipase A2α-mediated arachidonic acid release in intact platelets: variation of the keto moiety

“…The structure -activity relationships of the 3-acylindole-2-carboxylic acids discussed in preceding papers [14,16,27,28] were extended to the variation of the keto moiety of the 3-acyl residue. Replacing the 3-dodecanoyl substituent of 3-dodecanoyl-1-methylindole-2-carboxylic acid (1) by dodecylsulfinyl (9), dodecylsulfonyl (11), dodecylsulfinamoyl (13), dodecylsulfamoyl (15), dodecanoylamino (19), and dodecanoylaminomethyl (20), respectively, did not lead to a substantial change of inhibitory potency in the whole cell cPLA 2 a assay.…”

Phospholipases A2 and platelet-activating-factor acetylhydrolase in patients with acute respiratory distress syndrome*

“…Additional experiments of measuring PLA 2 activities of plasma, BAL, and BAL cells of patients with ARDS in the presence of specific inhibitors were also performed. The compounds LY311727 (3-[3-acetamide-1-benzyl-2-ethylindole-5-oxy] propane sulfonic acid), a specific inhibitor for type II secretory PLA 2 (18) and ML3176 (1-[2-ethyl]-3-dodecanoylindole-2-carboxylic acid), a specific inhibitor for cytosolic PLA 2 (19), were used in ethanol solutions. The sample had been preincubated with 25 M final concentration of each inhibitor for 20 mins at room temperature before the initiation of the reaction.…”

Inhibition of Cytosolic Phospholipase A2α: Hit to Lead Optimization

“…These inhibitors range from electrophilic ketones, such as the trifluoromethyl ketone of arachdonic acid, − to natural products , that inhibit cPLA 2 α, to compounds that are purported to have dual cPLA 2 α and sPLA 2 activity. Merckle − disclosed one of the first series of compounds thought to be inhibitors of cPLA 2 α. Elan has patented a group of cPLA 2 α inhibitors generated from pyrimidones. Shionogi − has reported on a series of pyrrolidine-based inhibitors that are among the most potent cPLA 2 α inhibitors disclosed.…”