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.
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.
Griessbach
Klaus
K
Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Hittorfstrasse 58-62, D-48149 Münster, Germany.
Klimt
Monika
M
Schulze Elfringhoff
Alwine
A
Lehr
Matthias
M
D016718:Arachidonic Acid / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D054467:Phospholipases A2; D013329:Structure-Activity Relationship
D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D007211:Indoles; D016718:Arachidonic Acid; D000001:Calcimycin; D010741:Phospholipases A; D054467:Phospholipases A2