Structure-activity relationship studies on 1-(2-oxopropyl)indole-5-carboxylic acids acting as inhibitors of cytosolic phospholipase A2α: Effect of substituents at the indole 3-position on activity, solubility, and metabolic stability.
Cytosolic phospholipase A2α (cPLA2α) is a key enzyme in the biosynthesis of pro-inflammatory lipid mediators and therefore represents an attractive target for the development of new anti-inflammatory drugs. Recently, we have found that 1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid (4) is a potent inhibitor of the enzyme. In this work, we evaluate the effect of butanoyl- and hexanoyl-substituents in position 3 of the indole scaffold of this compound bearing terminal groups of varying polarity. As a result, inhibitory potency was not affected considerably in most cases, while metabolic phase I and phase II in vitro stability and aqueous solubility could be influenced and modulated by the structural modifications performed.
Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrrensstr. 48, 48149 Münster, Germany.
Martina
M
Arnsmann
Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrrensstr. 48, 48149 Münster, Germany.
Walburga
W
Hanekamp
Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrrensstr. 48, 48149 Münster, Germany.
Alwine Schulze
AS
Elfringhoff
Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrrensstr. 48, 48149 Münster, Germany. Electronic address: lehrm@uni-muenster.de.
Matthias
M
Lehr
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D002264:Carboxylic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D064801:Phospholipase A2 Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship
D002264:Carboxylic Acids; D007211:Indoles; D064801:Phospholipase A2 Inhibitors; D054513:Group IV Phospholipases A2
Aqueous solubility; Cytosolic phospholipase A(2)α; Glucuronidation; Indole derivatives; Inhibitors; Ketone reduction; Metabolic stability