title: Investigations on the metabolic stability of cytosolic phospholipase A2α inhibitors with 1-indolylpropan-2-one structure.
abstract: Cytosolic phospholipase A2α (cPLA2α) plays a key role in the pathogenesis of many inflammatory diseases, such as rheumatoid arthritis, atopic dermatitis and Alzheimer's disease. Therefore, inhibition of this enzyme is assumed to provide a novel therapeutic option for the treatment of these maladies. In this study we investigated the metabolism of the potent cPLA2α inhibitors 1-[3-(4-phenoxyphenoxy)-2-oxopropyl]indole-5-carboxylic acid (1) and 3-isobutanoyl-1-[3-(4-phenoxyphenoxy)-2-oxopropyl]indole-5-carboxylic acid (2). Incubation of 1 with a mixture of human recombinant CYP1A2, 2C8, 2C9, 2C19, 2D6, 3A4 and NADPH-cytochrome P450 reductase enzymes led to reduction of its keto group and to hydroxylation at the terminal phenoxy residue. To identify the enzymes responsible for the observed reactions, experiments with isoform inhibitors were performed. In rat liver S9 fractions the only metabolite found was the alcohol 3 formed by the reduction of the keto group of 1. This reaction here was mainly catalyzed by cytosolic short-chain dehydrogenases/reductases (cSDR) as shown by inhibition experiments with different carbonyl reductase inhibitors. Furthermore, the metabolic stability of 2 in mouse brains was studied after intracerebroventricular application of this compound into the right brain hemispheres of mice. HPLC/MS analyses revealed that 2 is also readily reduced in the brain to an inactive alcohol metabolite most likely by carbonyl reductases.
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstrasse 48, 48149 Münster, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Fabian
authors.forename: Walburga
authors.initials: W
authors.lastname: Hanekamp
authors.forename: Mélanie H
authors.initials: MH
authors.lastname: Thomas
authors.forename: Jean Luc
authors.initials: JL
authors.lastname: Olivier
authors.forename: Matthias
authors.initials: M
authors.lastname: Lehr
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D010647:Phenyl Ethers / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C585955:1-(3-(4-phenoxyphenoxy)-2-oxopropyl)indole-5-carboxylic acid; C551617:3-isobutanoyl-1-(2-oxo-3-(4-phenoxyphenoxy)propyl)indole-5-carboxylic acid; D004791:Enzyme Inhibitors; D007211:Indoles; D010647:Phenyl Ethers; D011994:Recombinant Proteins; C030374:indole; D003577:Cytochrome P-450 Enzyme System; D019388:Cytochrome P-450 CYP1A2; D054513:Group IV Phospholipases A2
keywords: AKR; CYP450; Carbonyl reductase; Cytosolic phospholipase A(2)α; ESI; HPLC; HRMS; Inhibitor; MS; Metabolism; Mouse brain; NMR; Rat S9 fractions; SDR; aldo–keto-reductase; cPLA(2)α; cytochrome P450; cytosolic phospholipase A(2)α; electrospray ionization; high performance liquid chromatography; high resolution mass spectrometry; mass spectrometry; nuclear magnetic resonance spectrometry; short-chain dehydrogenase/reductase