ABSTRACT
Indole-5-carboxylic acids with 3-aryloxy-2-oxopropyl residues in position 1 have been found to be potent inhibitors of human cytosolic phospholipase A(2)α (cPLA(2)α). In course of structure-activity relationship studies, we investigated the effect of the substitution of the electrophilic ketone group in the middle part of the molecule by other polar residues, such as hydroxyimino, azido, acyloxy, acylamino, urea and carbamate, on enzyme inhibition. With an IC(50) of 1.7 µM against cPLA(2)α from human platelets, the 4-fluorophenylcarbamate derivative 23f was the most active of the compounds tested.
Subject(s)
Cytosol/enzymology , Ketones/metabolism , Phospholipases A2/metabolism , Humans , Structure-Activity RelationshipABSTRACT
Indole-5-carboxylic acids with 3-aryloxy-2-oxopropyl residues in position 1 have been found to be potent inhibitors of human cytosolic phospholipase A2α (cPLA2α). In the course of structure-activity relationship studies, we investigated the effect of a substitution of indole 3 position with acyl, alkyl, and oxadiazole residues. The highest increase of inhibitory potency could be achieved by a 3-methyl-1,2,4-oxadiazol-5-yl-moiety. Appropriate compound 40 revealed an IC50 of 0.0021 µM against isolated cPLA2α. In a cellular assay applying human platelets 40 blocked cPLA2α activity even with an IC50 of 0.0006 µM. Metabolic stability and aqueous solubility of the target compounds were also determined. Furthermore, one selected compound was tested for peroral bioavailability in mice.
Subject(s)
Group IV Phospholipases A2/antagonists & inhibitors , Indoles/chemistry , Oxadiazoles/pharmacology , Phospholipase A2 Inhibitors/pharmacology , Animals , Biological Availability , Humans , Indoles/pharmacology , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Mice , Mice, Inbred C57BL , Oxadiazoles/chemistry , Phospholipase A2 Inhibitors/chemistry , Phospholipase A2 Inhibitors/pharmacokinetics , Solubility , Spectrometry, Mass, Electrospray IonizationABSTRACT
Cytosolic phospholipase A(2)alpha (cPLA(2)alpha) and fatty acid amide hydrolase (FAAH) are enzymes, which have emerged as attractive targets for the development of analgetic and anti-inflammatory drugs. We recently reported that 1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid (10) and related compounds are inhibitors of cPLA(2)alpha. Since cPLA(2)alpha and FAAH possess several common structural features, we now screened this substance series together with some new derivatives for FAAH inhibition. Some of the assayed compounds proved to be selective cPLA(2)alpha inhibitors, while others showed high FAAH and moderate cPLA(2)alpha inhibitory potency. Furthermore, several derivatives were favorably active against both enzymes and, therefore, could represent agents, which have improved analgetic and anti-inflammatory qualities in comparison with selective cPLA(2)alpha and FAAH inhibitors.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Group IV Phospholipases A2/antagonists & inhibitors , Heterocyclic Compounds/pharmacology , Indoles/pharmacology , Amidohydrolases/metabolism , Animals , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Group IV Phospholipases A2/isolation & purification , Group IV Phospholipases A2/metabolism , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Humans , Indoles/chemical synthesis , Indoles/chemistry , Molecular Conformation , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The indole ring systems of the cytosolic phospholipase A(2)alpha (cPLA(2)alpha) inhibitor 1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid (2) and the isomeric 6-carboxylic acid (3) were replaced by benzimidazole, benzotriazole and indazole scaffolds, respectively. The effect of the structural variations on cPLA(2)alpha inhibitory potency, metabolic stability and solubility was studied. The lead 2 and the indazole-5-carboxylic acid 28 were the metabolically most stable compounds in an assay with rat liver microsomes, while the benzimidazole-5-carboxylic acid derivative 13 possessed the best water solubility (22 microg/mL at pH 7.4). The indazole-5-carboxylic acid 28 revealed the highest cPLA(2)alpha inhibitory potency of the compounds in this series. With an IC(50)-value of 0.005 microM it was about sevenfold more active than the lead 2.
