High-performance liquid chromatographic assay with ultraviolet spectrometric detection for the evaluation of inhibitors of secretory phospholipase A2

1-(5-Carboxyindol-1-yl)propan-2-one Inhibitors of Human Cytosolic Phospholipase A2α with Reduced Lipophilicity: Synthesis, Biological Activity, Metabolic Stability, Solubility, Bioavailability, And Topical in Vivo Activity

“…To evaluate selectivity of 36 for inhibition of cPLA 2 α, inhibitory potency of this compound against calcium-independent PLA 2 (iPLA 2 ) from rat brain cytosol as well as group IB secretory PLA 2 (sPLA 2 ) from porcine pancreas was determined. , At a concentration of 10 μM, compound 36 did not affect activity of these two PLA 2 enzymes. In contrast, at this concentration, the iPLA 2 inhibitor bromoenol lactone produced an about 50% inhibition of iPLA 2 activity, and the sPLA 2 inhibitor ( S )-5-(4-benzyloxyphenyl)-4-[(7-phenylheptanoyl)amino]pentanoic acid blocked activity of group IB sPLA 2 by 89% ( n = 2) (see Supporting Information for more information).…”

1-(5-Carboxyindol-1-yl)propan-2-one Inhibitors of Human Cytosolic Phospholipase A2α: Effect of Substituents in Position 3 of the Indole Scaffold on Inhibitory Potency, Metabolic Stability, Solubility, and Bioavailability

“…To obtain some information about specifity of 30 for cPLA 2 α inhibition, we examined its inhibitory potency toward other PLA 2 enzymes, namely, calcium-independent PLA 2 (iPLA 2 ) from rat brain cytosol and group IB secretory PLA 2 (sPLA 2 ) from porcine pancreas. , At the highest test concentration of 10 μM, 30 did not inhibit these enzymes, while the applied reference inhibitors for iPLA 2 (bromoenol lactone) and sPLA 2 (( S )-5-(4-benzyloxyphenyl)-4-[(7-phenylheptanoyl)amino]pentanoic acid) showed about 50% and 90% enzyme inhibition, respectively, at this concentration.…”

“…Inhibition of iPLA 2 in rat brain cytosol and sPLA 2 from porcine pancreas (group IB) by 30 was assessed by the methods described recently. ,, Briefly, in the case of iPLA 2 , 1-palmitoyl-2-(10-pyren-1-yldecanoyl)- sn -glycero-3-phosphocholine was used as substrate. Enzyme activity in the presence and absence of the test compound was determined by measuring the release of 10-pyren-1-yldecanoic acid by reversed phase HPLC and fluorescence detection.…”

“…tert-Butyl 3-(3-Methyl-1,2,4-oxadiazol-5-yl)-1-oxiranylmethylindole-5-carboxylate (37). Compound 36 (305 mg, 1.0 mmol) was reacted with epichlorohydrin as described for the preparation of compound 7.…”