کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5848138 1130137 2013 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Investigations on the metabolic stability of cytosolic phospholipase A2α inhibitors with 1-indolylpropan-2-one structure
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم محیط زیست بهداشت، سم شناسی و جهش زایی
پیش نمایش صفحه اول مقاله
Investigations on the metabolic stability of cytosolic phospholipase A2α inhibitors with 1-indolylpropan-2-one structure
چکیده انگلیسی
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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Chemico-Biological Interactions - Volume 206, Issue 2, 25 November 2013, Pages 356-363
نویسندگان
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