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Eur J Med Chem. 2017 Jan 5;125:1107-1114. doi: 10.1016/j.ejmech.2016.10.039. Epub 2016 Oct 21.

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.

Author information

1
Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrrensstr. 48, 48149 Münster, Germany.
2
Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrrensstr. 48, 48149 Münster, Germany. Electronic address: lehrm@uni-muenster.de.

Abstract

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.

KEYWORDS:

Aqueous solubility; Cytosolic phospholipase A(2)α; Glucuronidation; Indole derivatives; Inhibitors; Ketone reduction; Metabolic stability

PMID:
27810597
DOI:
10.1016/j.ejmech.2016.10.039
[Indexed for MEDLINE]

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